Publications by authors named "Kathleen D Liu"

215 Publications

Recovery after Critical Illness and Acute Kidney Injury.

Clin J Am Soc Nephrol 2021 Aug 30. Epub 2021 Aug 30.

Department of Medicine, Albany Medical College, Albany, New York.

AKI is a common complication in hospitalized and critically ill patients. Its incidence has steadily increased over the past decade. Whether transient or prolonged, AKI is an independent risk factor associated with poor short- and long-term outcomes, even if patients do not require KRT. Most patients with early AKI improve with conservative management; however, some will require dialysis for a few days, a few weeks, or even months. Approximately 10%-30% of AKI survivors may still need dialysis after hospital discharge. These patients have a higher associated risk of death, rehospitalization, recurrent AKI, and CKD, and a lower quality of life. Survivors of critical illness may also suffer from cognitive dysfunction, muscle weakness, prolonged ventilator dependence, malnutrition, infections, chronic pain, and poor wound healing. Collaboration and communication among nephrologists, primary care physicians, rehabilitation providers, physical therapists, nutritionists, nurses, pharmacists, and other members of the health care team are essential to create a holistic and patient-centric care plan for overall recovery. Integration of the patient and family members in health care decisions, and ongoing education throughout the process, are vital to improve patient well-being. From the nephrologist standpoint, assessing and promoting recovery of kidney function, and providing appropriate short- and long-term follow-up, are crucial to prevent rehospitalizations and to reduce complications. Return to baseline functional status is the ultimate goal for most patients, and dialysis independence is an important part of that goal. In this review, we seek to highlight the varying aspects and stages of recovery from AKI complicating critical illness, and propose viable strategies to promote recovery of kidney function and dialysis independence. We also emphasize the need for ongoing research and multidisciplinary collaboration to improve outcomes in this vulnerable population.
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http://dx.doi.org/10.2215/CJN.19601220DOI Listing
August 2021

Plasma Metabolites in Early Sepsis Identify Distinct Clusters Defined by Plasma Lipids.

Crit Care Explor 2021 Aug 29;3(8):e0478. Epub 2021 Jul 29.

Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, CA.

Unbiased global metabolomic profiling has not been used to identify distinct subclasses in patients with early sepsis and sepsis-associated acute respiratory distress syndrome. In this study, we examined whether the plasma metabolome reflects systemic illness in early sepsis and in acute respiratory distress syndrome.

Design: Plasma metabolites were measured in subjects with early sepsis.

Setting: Patients were admitted from the emergency department to the ICU in a plasma sample collected within 24 hours of ICU admission. Metabolic profiling of 970 metabolites was performed by Metabolon (Durham, NC). Hierarchical clustering and partial least squares discriminant clustering were used to identify distinct clusters among patients with early sepsis and sepsis-associated acute respiratory distress syndrome.

Interventions: None.

Measurements And Main Results: Among critically ill patients with early sepsis ( = 197), three metabolically distinct subgroups were identified, with metabolic subtype driven by plasma lipids. Group 1, with 45 subjects (23% of cohort), had increased 60-day mortality (odds ratio, 2; 95% CI, 0.99-4.0; = 0.04 for group 1 vs all others). This group also had higher rates of vasopressor-dependent shock, acute kidney injury, and met Berlin acute respiratory distress syndrome criteria more often (all < 0.05). Conversely, metabolic group 3, with 76 subjects (39% of cohort), had the lowest risk of 60-day mortality (odds ratio, 0.44; 95% CI, 0.22-0.86; = 0.01) and lower rates of organ dysfunction as reflected in a lower Simplified Acute Physiology Score II ( < 0.001). In contrast, global metabolomic profiling did not separate patient with early sepsis with moderate-to-severe acute respiratory distress syndrome ( = 78) from those with sepsis without acute respiratory distress syndrome ( = 75).

Conclusions: Plasma metabolomic profiling in patients with early sepsis identified three metabolically distinct groups that were characterized by different plasma lipid profiles, distinct clinical phenotypes, and 60-day mortality. Plasma metabolites did not distinguish patients with early sepsis who developed acute respiratory distress syndrome from those who did not.
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http://dx.doi.org/10.1097/CCE.0000000000000478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323800PMC
August 2021

Identifying the Sickest During Triage: Using Point-of-Care Severity Scores to Predict Prognosis in Emergency Department Patients With Suspected Sepsis.

J Hosp Med 2021 Aug;16(8):453-461

Division of Hospital Medicine, Department of Medicine, University of California, San Francisco, California.

Background: Sepsis progresses rapidly and is associated with considerable morbidity and mortality. Bedside risk stratification scores can quickly identify patients at greatest risk of poor outcomes; however, there is lack of consensus on the best scale to use.

Objective: To compare the ability of quick Sequential Organ Failure Assessment (qSOFA), the National Early Warning System (NEWS2), and the Shock Index-which does not require mental status assessment-to predict poor outcomes among patients with suspected sepsis during triage.

Design, Setting, And Participants: Retrospective cohort study of adults presenting to an academic emergency department (ED) from June 2012 to December 2018 who had blood cultures and intravenous antibiotics within 24 hours.

Main Outcomes And Measures: Clinical data were collected from the electronic health record. Patients were considered positive at qSOFA ≥2, Shock Index >0.7, or NEWS2 ≥5 scores. We calculated test characteristics and area under the receiver operating characteristics curves (AUROCs) to predict in-hospital mortality and ED-to-intensive care unit (ICU) admission.

Results: We included 23,837 ED patients; 1,921(8.1%) were qSOFA-positive, 4,273 (17.9%) Shock Index-positive, and 11,832 (49.6%) NEWS2-positive. There were 1,427 (6.0%) deaths and 3,149 (13.2%) ED-to-ICU admissions in the sample. NEWS2 had the highest sensitivity for in-hospital mortality (76.0%) and ED-to-ICU admission (78.9%). qSOFA had the highest specificity for in-hospital mortality (93.4%) and ED-to-ICU admission (95.2%). Shock Index exhibited the highest AUROC for in-hospital mortality (0.648; 95 CI, 0.635-0.662) and ED-to-ICU admission (0.680; 95% CI, 0.617-0.689). Test characteristics were similar among those with sepsis.

Conclusions: Institution priorities should drive score selection, balancing sensitivity and specificity. In our study, qSOFA was highly specific and NEWS2 was the most sensitive for ruling out patients at high risk. Performance of the Shock Index fell between qSOFA and NEWS2 and could be considered because it is easy to implement.
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http://dx.doi.org/10.12788/jhm.3642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340957PMC
August 2021

Achieved blood pressure post-acute kidney injury and risk of adverse outcomes after AKI: A prospective parallel cohort study.

BMC Nephrol 2021 Jul 29;22(1):270. Epub 2021 Jul 29.

Division of Nephrology, University of California, San Francisco School of Medicine, San Francisco, CA, USA.

Background: There has recently been considerable interest in better understanding how blood pressure should be managed after an episode of hospitalized AKI, but there are scant data regarding the associations between blood pressure measured after AKI and subsequent adverse outcomes. We hypothesized that among AKI survivors, higher blood pressure measured three months after hospital discharge would be associated with worse outcomes. We also hypothesized these associations between blood pressure and outcomes would be similar among those who survived non-AKI hospitalizations.

Methods: We quantified how systolic blood pressure (SBP) observed three months after hospital discharge was associated with risks of subsequent hospitalized AKI, loss of kidney function, mortality, and heart failure events among 769 patients in the prospective ASSESS-AKI cohort study who had hospitalized AKI. We repeated this analysis among the 769 matched non-AKI ASSESS-AKI enrollees. We then formally tested for AKI interaction in the full cohort of 1538 patients to determine if these associations differed among those who did and did not experience AKI during the index hospitalization.

Results: Among 769 patients with AKI, 42 % had subsequent AKI, 13 % had loss of kidney function, 27 % died, and 18 % had heart failure events. SBP 3 months post-hospitalization did not have a stepwise association with the risk of subsequent AKI, loss of kidney function, mortality, or heart failure events. Among the 769 without AKI, there was also no stepwise association with these risks. In formal interaction testing using the full cohort of 1538 patients, hospitalized AKI did not modify the association between post-discharge SBP and subsequent risks of adverse clinical outcomes.

Conclusions: Contrary to our first hypothesis, we did not observe that higher stepwise blood pressure measured three months after hospital discharge with AKI was associated with worse outcomes. Our data were consistent with our second hypothesis that the association between blood pressure measured three months after hospital discharge and outcomes among AKI survivors is similar to that observed among those who survived non-AKI hospitalizations.
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http://dx.doi.org/10.1186/s12882-021-02480-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320241PMC
July 2021

Association Between Kidney Dysfunction Types and Mortality Among Hospitalized Patients with Cirrhosis.

Dig Dis Sci 2021 Jul 22. Epub 2021 Jul 22.

Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA.

Background And Aims: Kidney dysfunction is associated with increased mortality among patients with cirrhosis. We investigated whether kidney dysfunction types [e.g., acute kidney injury (AKI), chronic kidney disease (CKD), and AKI on CKD] were differentially associated with inpatient mortality.

Methods: We utilized the nationwide inpatient sample, a nationally representative database, from 2007 to 2014. We included all hospitalizations with previously validated codes for cirrhosis or associated decompensated cirrhosis diagnoses. We defined kidney dysfunction types also from previously validated codes, and we grouped hospitalizations into the following diagnoses: normal, AKI, CKD, and AKI on CKD. Our primary outcome was inpatient mortality.

Results: There were 1,293,779 hospitalizations with cirrhosis sampled in this study. Of these hospitalizations, 849,193 (66%) had normal kidney function, 176,418 (14%) had AKI, 157,600 (12%) had CKD, and 110,568 (9%) had AKI on CKD. We found that the proportion of hospitalizations with AKI, CKD, and AKI on CKD increased significantly throughout the study period (p < 0.001, test for trend for all). Kidney dysfunction type was differentially associated with inpatient mortality, even after adjustment: as compared to those with CKD, normal kidney function: OR 0.75 [95 CI 0.73-0.78], AKI: OR 2.40 [95 CI 2.32-2.48], and AKI on CKD: OR 1.66 [95 CI 1.60-1.72].

Discussion: Using a nationally representative cohort of all hospitalizations with cirrhosis, our study highlights that the burden of kidney dysfunction, especially AKI, among hospitalizations with cirrhosis is rising, and the inclusion of kidney dysfunction type may be an opportunity to improve prognostication.
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http://dx.doi.org/10.1007/s10620-021-07159-zDOI Listing
July 2021

Latent class analysis-derived subphenotypes are generalisable to observational cohorts of acute respiratory distress syndrome: a prospective study.

Thorax 2021 Jul 12. Epub 2021 Jul 12.

Department of Anesthesiology, University of California San Francisco, San Francisco, California, USA.

Rationale: Using latent class analysis (LCA), two subphenotypes of acute respiratory distress syndrome (ARDS) have consistently been identified in five randomised controlled trials (RCTs), with distinct biological characteristics, divergent outcomes and differential treatment responses to randomised interventions. Their existence in unselected populations of ARDS remains unknown. We sought to identify subphenotypes in observational cohorts of ARDS using LCA.

Methods: LCA was independently applied to patients with ARDS from two prospective observational cohorts of patients admitted to the intensive care unit, derived from the Validating Acute Lung Injury markers for Diagnosis (VALID) (n=624) and Early Assessment of Renal and Lung Injury (EARLI) (n=335) studies. Clinical and biological data were used as class-defining variables. To test for concordance with prior ARDS subphenotypes, the performance metrics of parsimonious classifier models (interleukin 8, bicarbonate, protein C and vasopressor-use), previously developed in RCTs, were evaluated in EARLI and VALID with LCA-derived subphenotypes as the gold-standard.

Results: A 2-class model best fit the population in VALID (p=0.0010) and in EARLI (p<0.0001). Class 2 comprised 27% and 37% of the populations in VALID and EARLI, respectively. Consistent with the previously described 'hyperinflammatory' subphenotype, Class 2 was characterised by higher proinflammatory biomarkers, acidosis and increased shock and worse clinical outcomes. The similarities between these and prior RCT-derived subphenotypes were further substantiated by the performance of the parsimonious classifier models in both cohorts (area under the curves 0.92-0.94). The hyperinflammatory subphenotype was associated with increased prevalence of chronic liver disease and neutropenia and reduced incidence of chronic obstructive pulmonary disease. Measurement of novel biomarkers showed significantly higher levels of matrix metalloproteinase-8 and markers of endothelial injury in the hyperinflammatory subphenotype, whereas, matrix metalloproteinase-9 was significantly lower.

Conclusion: Previously described subphenotypes are generalisable to unselected populations of non-trauma ARDS.
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http://dx.doi.org/10.1136/thoraxjnl-2021-217158DOI Listing
July 2021

Kidney Replacement Therapy in the ICU: Less Is More (Death)?

Am J Kidney Dis 2021 Jul 7. Epub 2021 Jul 7.

Division of Critical Care Medicine, Department of Anesthesia and Perioperative Care, University of California, San Francisco; Division of Nephrology, Department of Medicine, University of California, San Francisco.

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http://dx.doi.org/10.1053/j.ajkd.2021.06.011DOI Listing
July 2021

Plasma Kidney Injury Molecule 1 in CKD: Findings From the Boston Kidney Biopsy Cohort and CRIC Studies.

Am J Kidney Dis 2021 Jun 24. Epub 2021 Jun 24.

Section of Nephrology, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, MA; Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Electronic address:

Rationale & Objective: Plasma kidney injury molecule-1 (KIM-1) is a sensitive marker of proximal tubule injury, but its association with risks of adverse clinical outcomes across a spectrum of kidney diseases is unknown.

Study Design: Prospective, observational cohort study.

Setting & Participants: 524 individuals undergoing clinically indicated native kidney biopsy with biopsy specimens adjudicated for semiquantitative scores of histopathology by two kidney pathologists enrolled into the Boston Kidney Biopsy Cohort (BKBC) Study and 3,800 individuals with common forms of chronic kidney disease (CKD) enrolled into the Chronic Renal Insufficiency Cohort (CRIC) Study.

Exposure: Histopathologic lesions and clinicopathologic diagnosis in cross-sectional analyses, baseline plasma KIM-1 in prospective analyses.

Outcomes: Baseline plasma KIM-1 in cross-sectional analyses, kidney failure (defined as initiation of kidney replacement therapy) and death in prospective analyses.

Analytical Approach: Multivariable-adjusted linear regression models tested associations of plasma KIM-1 with histopathologic lesions and clinicopathologic diagnoses. Cox proportional hazards models tested associations of plasma KIM-1 with future kidney failure and death.

Results: In the BKBC Study, higher plasma KIM-levels were associated with more severe acute tubular injury, tubulointerstitial inflammation, and more severe mesangial expansion after multivariable adjustment. Participants with diabetic nephropathy, glomerulopathies, and tubulointerstitial disease had significantly higher plasma KIM-1 levels after multivariable adjustment. In the BKBC Study, 124 participants progressed to kidney failure and 85 participants died during a median follow-up time of 5 years. In the CRIC Study, 1153 participants progressed to kidney failure and 1356 participants died during a median follow-up time of 11.5 years. In both cohorts, each doubling of plasma KIM-1 was associated with an increased risk of kidney failure after multivariable adjustment (BKBC: HR 1.19, 95% CI 1.03 to 1.38 and CRIC: HR 1.10, 95% CI 1.06 to 1.15). There was no statistically significant association of plasma KIM-1 with death in either cohort.

Limitations: Generalizability and unmeasured confounding.

Conclusions: Plasma KIM-1 is associated with underlying tubulointerstitial and mesangial lesions and progression to kidney failure in two cohort studies of individuals with kidney diseases.
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http://dx.doi.org/10.1053/j.ajkd.2021.05.013DOI Listing
June 2021

Changes in intensive care unit admission rates, organ support, and mortality in patients with acute myeloid leukaemia over a 12-year period: a Danish nationwide cohort study.

Br J Haematol 2021 Jun 7. Epub 2021 Jun 7.

Division of Nephrology, Departments of Medicine and Anaesthesia, University of California San Francisco, San Francisco, CA, USA.

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http://dx.doi.org/10.1111/bjh.17630DOI Listing
June 2021

Postoperative acute kidney injury in adult non-cardiac surgery: joint consensus report of the Acute Disease Quality Initiative and PeriOperative Quality Initiative.

Nat Rev Nephrol 2021 09 11;17(9):605-618. Epub 2021 May 11.

Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research.
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http://dx.doi.org/10.1038/s41581-021-00418-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367817PMC
September 2021

Survey of Current Practices of Outpatient Hemodialysis for AKI Patients.

Kidney Int Rep 2021 Apr 28;6(4):1156-1160. Epub 2021 Jan 28.

Department of Internal Medicine, Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky Medical Center, Lexington, Kentucky, USA.

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http://dx.doi.org/10.1016/j.ekir.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071612PMC
April 2021

Healthy inflamed lung environments differentially effect MSCs.

Eur Respir J 2021 Apr 1. Epub 2021 Apr 1.

Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.

Background: Despite increased interest in MSC-based cell therapies for the acute respiratory distress syndrome (ARDS), clinical investigations have not yet been successful and understanding of the potential mechanisms of MSC actions in ARDS remain limited. ARDS is driven by an acute severe innate immune dysregulation, often characterised by inflammation, coagulation, and cell injury. How this inflammatory microenvironment influences MSC functions remains to be determined.

Aim: To comparatively assess how the inflammatory environment present in ARDS lungs the lung environment present in healthy volunteers alters MSC behaviors.

Methods: Clinical grade human bone marrow-derived MSCs (hMSCs) were exposed to bronchoalveolar lavage fluid (BALF) samples obtained from ARDS patients or from healthy volunteers. Following exposure, hMSCs and their conditioned media were evaluated for a broad panel of relevant properties including viability, levels of expression of inflammatory cytokines, gene expression, cell surface HLA expression, and activation of coagulation and complement pathways.

Results: Pro-inflammatory, pro-coagulant, and major histocompatibility complex (self recognition) related gene expression was markedly up-regulated in hMSCs exposed to BALF obtained from healthy volunteers. In contrast, these changes were less apparent and often opposite in hMSCs exposed to ARDS BALF samples.

Conclusion: These data provide new insights into how hMSCs behave in healthy inflamed lung environments strongly suggesting that the inflamed environment in ARDS induces hMSC responses potentially benefical for cell survival and actions. This further highlights the need to understand how different disease environments affect hMSC functions.
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http://dx.doi.org/10.1183/13993003.04149-2020DOI Listing
April 2021

Recovery of kidney function after dialysis initiation in children and adults in the US: A retrospective study of United States Renal Data System data.

PLoS Med 2021 02 19;18(2):e1003546. Epub 2021 Feb 19.

University of California San Francisco, Division of Nephrology, Department of Medicine, San Francisco, California, United States of America.

Background: Little is known about factors associated with recovery of kidney function-and return to dialysis independence-or temporal trends in recovery after starting outpatient dialysis in the United States. Understanding the characteristics of individuals who may have the potential to recover kidney function may promote better recognition of such events. The goal of this study was to determine factors associated with recovery of kidney function in children compared with adults starting dialysis in the US.

Methods And Findings: We determined factors associated with recovery of kidney function-defined as survival and discontinuation of dialysis for ≥90-day period-in children versus adults who started maintenance dialysis between 1996 and 2015 according to the United States Renal Data System (USRDS) followed through 2016 in a retrospective cohort study. We also examined temporal trends in recovery rates over the last 2 decades in this cohort. Among 1,968,253 individuals included for study, the mean age was 62.6 ± 15.8 years, and 44% were female. Overall, 4% of adults (83,302/1,953,881) and 4% of children (547/14,372) starting dialysis in the outpatient setting recovered kidney function within 1 year. Among those who recovered, the median time to recovery was 73 days (interquartile range [IQR] 43-131) in adults and 100 days (IQR 56-189) in children. Accounting for the competing risk of death, children were less likely to recover kidney function compared with adults (sub-hazard ratio [sub-HR] 0.81; 95% CI 0.74-0.89, p-value <0.001; point estimates <1 indicating increased risk for a negative outcome). Non-Hispanic black (NHB) adults were less likely to recover compared with non-Hispanic white (NHW) adults, but these racial differences were not observed in children. Of note, a steady increase in the incidence of recovery of kidney function was noted initially in adults and children between 1996 and 2010, but this trend declined thereafter. The diagnoses associated with the highest recovery rates of recovery were acute tubular necrosis (ATN) and acute interstitial nephritis (AIN) in both adults and children, where 25%-40% of patients recovered kidney function depending on the calendar year of dialysis initiation. Limitations to our study include the potential for residual confounding to be present given the observational nature of our data.

Conclusions: In this study, we observed that discontinuation of outpatient dialysis due to recovery occurred in 4% of patients with end-stage kidney disease (ESKD) and was more common among those with ATN or AIN as the cause of their kidney disease. While recovery rates rose initially, they declined starting in 2010. Additional studies are needed to understand how to best recognize and promote recovery in patients whose potential to discontinue dialysis is high in the outpatient setting.
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http://dx.doi.org/10.1371/journal.pmed.1003546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935284PMC
February 2021

Outpatient Dietary Management of Electrolyte Disorders During COVID-19: Food as Medicine.

JAMA Intern Med 2021 05;181(5):581-582

Division of Nephrology, Department of Medicine, School of Medicine, University of California, San Francisco.

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http://dx.doi.org/10.1001/jamainternmed.2020.8897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096698PMC
May 2021

A neutrophil subset defined by intracellular olfactomedin 4 is associated with mortality in sepsis.

Am J Physiol Lung Cell Mol Physiol 2021 05 23;320(5):L892-L902. Epub 2020 Dec 23.

Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California.

Sepsis is a heterogeneous syndrome clinically and biologically, but biomarkers of distinct host response pathways for early prognostic information and testing targeted treatments are lacking. Olfactomedin 4 (), a matrix glycoprotein of neutrophil-specific granules, defines a distinct neutrophil subset that may be an independent risk factor for poor outcomes in sepsis. We hypothesized that increased percentage of OLFM4 neutrophils on sepsis presentation would be associated with mortality. In a single-center, prospective cohort study, we enrolled adults admitted to an academic medical center from the emergency department (ED) with suspected sepsis [identified by 2 or greater systemic inflammatory response syndrome (SIRS) criteria and antibiotic receipt] from March 2016 through December 2017, followed by sepsis adjudication according to Sepsis-3. We collected 200 µL of whole blood within 24 h of admission and stained for the neutrophil surface marker CD66b followed by intracellular staining for OLFM4 quantitated by flow cytometry. The predictors for 60-day mortality were ) percentage of OLFM4 neutrophils and ) OLFM4 neutrophils at a cut point of ≥37.6% determined by the Youden Index. Of 120 enrolled patients with suspected sepsis, 97 had sepsis and 23 had nonsepsis SIRS. The mean percentage of OLFM4 neutrophils was significantly increased in both sepsis and nonsepsis SIRS patients who died ( ≤ 0.01). Among sepsis patients with elevated OLFM4 (≥37.6%), 56% died, compared with 18% with OLFM4 <37.6% ( = 0.001). The association between OLFM4 and mortality withstood adjustment for age, sex, absolute neutrophil count, comorbidities, and standard measures of severity of illness (SOFA score, APACHE III) ( < 0.03). In summary, OLFM4 neutrophil percentage is independently associated with 60-day mortality in sepsis and may represent a novel measure of the heterogeneity of host response to sepsis.
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http://dx.doi.org/10.1152/ajplung.00090.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174834PMC
May 2021

Effect of Low-Frequency Therapeutic Ultrasound on Induction of Nitric Oxide in CKD: Potential to Prevent Acute Kidney Injury.

Kidney Dis (Basel) 2020 Nov 21;6(6):453-460. Epub 2020 Aug 21.

Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, USA.

Introduction: Post-contrast acute kidney injury (PC-AKI) develops in a significant proportion of patients with CKD after invasive cardiology procedures and is strongly associated with adverse outcomes.

Objective: We sought to determine whether increased intrarenal nitric oxide (NO) would prevent PC-AKI.

Methods: To create a large animal model of CKD, we infused 250 micron particles into the renal arteries in 56 ± 8 kg pigs. We used a low-frequency therapeutic ultrasound device (LOTUS - 29 kHz, 0.4 W/cm) to induce NO release. NO and laser Doppler probes were used to assess changes in NO content and blood flow. Glomerular filtration rate (GFR) was measured by technetium-diethylene-triamine-pentaacetic acid (Tc-99m-DTPA) radionuclide imaging. PC-AKI was induced by intravenous infusion of 7 cm/kg diatrizoate. In patients with CKD, we measured GFR at baseline and during LOTUS using Tc-99m-DTPA radionuclide imaging.

Results: In the pig model, CKD developed over 4 weeks (serum creatinine [Cr], mg/dL, 1.0 ± 0.2-2.6 ± 0.9, < 0.01, = 12). NO and renal blood flow (RBF) increased in cortex and medulla during LOTUS. GFR increased 75 ± 24% ( = 0.016, = 3). PC-AKI developed following diatrizoate i.v. infusion (Cr 2.6 ± 0.7 baseline to 3.4 ± 0.6 at 24 h, < 0.01, = 3). LOTUS (starting 15 min prior to contrast and lasting for 90 min) prevented PC-AKI in the same animals 1 week later (Cr 2.5 ± 0.4 baseline to 2.6 ± 0.7 at 24 h, = ns, = 3). In patients with CKD ( = 10), there was an overall 25% increase in GFR in response to LOTUS ( < 0.01).

Conclusions: LOTUS increased intrarenal NO, RBF, and GFR and prevented PC-AKI in a large animal model of CKD, and significantly increased GFR in patients with CKD. This novel approach may provide a noninvasive nonpharmacological means to prevent PC-AKI in high-risk patients.
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http://dx.doi.org/10.1159/000509819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706515PMC
November 2020

Biomarkers of inflammation and repair in kidney disease progression.

J Clin Invest 2021 02;131(3)

Division of Nephrology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

INTRODUCTIONAcute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision making, more accurate information regarding risk of long-term progression to kidney failure is required.METHODSWe enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein 1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression.RESULTSHigher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis.CONCLUSIONSBiomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression.FUNDINGNIH.
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http://dx.doi.org/10.1172/JCI139927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843225PMC
February 2021

Prospective Cohort Study of Renin-Angiotensin System Blocker Usage after Hospitalized Acute Kidney Injury.

Clin J Am Soc Nephrol 2020 12 3;16(1):26-36. Epub 2020 Dec 3.

Division of Nephrology, University of California, San Francisco School of Medicine, San Francisco, California

Background And Objectives: The risk-benefit ratio of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy after AKI may be altered due to concerns regarding recurrent AKI. We evaluated, in a prospective cohort, the association between use (versus nonuse) of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and the subsequent risk of AKI and other adverse outcomes after hospitalizations with and without AKI.

Design, Setting, Participants, & Measurements: We studied 1538 patients recently discharged from the hospital who enrolled in the multicenter, prospective ASSESS-AKI study, with approximately half of patients experiencing AKI during the index hospitalization. All participants were seen at a baseline visit 3 months after their index hospitalization and were categorized at that time on whether they were using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or not. We used multivariable Cox regression, adjusting for demographics, comorbidities, eGFR, urine protein-creatinine ratio, and use of other medications, to examine the association between angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use and subsequent risks of AKI, death, kidney disease progression, and adjudicated heart-failure events.

Results: The use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was 50% (386/769) among those with AKI during the index hospitalization and 47% (362/769) among those without. Among those with AKI during the index hospitalization, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use was not associated with a higher risk of recurrent hospitalized AKI (adjusted hazard ratio, 0.88; 95% confidence interval, 0.69 to 1.13). Associations between angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use and death, kidney disease progression, and adjudicated heart-failure events appeared similar in study participants who did and did not experience AKI during the index hospitalization (all interaction values >0.05).

Conclusions: The risk-benefit ratio of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy after hospital discharge appears to be similar regardless of whether AKI occurred during the hospitalization.
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http://dx.doi.org/10.2215/CJN.10840720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792656PMC
December 2020

Alternative Tobacco Product Use in Critically Ill Patients.

Int J Environ Res Public Health 2020 11 24;17(23). Epub 2020 Nov 24.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA 94143, USA.

Alternative tobacco product (ATP) use has bee linked to critical illness, however, few studies have examined the use of these substances in critically ill populations. We sought to examine ATP use within critically ill patients and to define barriers in accurately assessing use within this population. We prospectively studied 533 consecutive patients from the Early Assessment of Renal and Lung Injury study, enrolled between 2013 and 2016 at a tertiary referral center and a safety-net hospital. ATP use information (electronic cigarettes, cigars, pipes, hookahs/waterpipes, and snus/chewing tobacco) was obtained from the patient or surrogate using a detailed survey. Reasons for non-completion of the survey were recorded, and differences between survey responders vs. non-responders, self- vs. surrogate responders, and ATP users vs. non-users were explored. Overall, 80% ( = 425) of subjects (56% male) completed a tobacco product use survey. Of these, 12.2% ( = 52) reported current ATP use, while 5.6% reported using multiple ATP products. When restricted to subjects who were self-responders, 17% reported ATP use, while 10% reported current cigarette smoking alone. The mean age of ATP users was 57 ± 17 years. Those who did not complete a survey were sicker and more likely to have died during admission. Subjects who completed the survey as self-responders reported higher levels of ATP use than ones with surrogate responders ( < 0.0001). ATP use is common among critically ill patients despite them being generally older than traditional users. Survey self-responders were more likely than surrogate responders to report use. These findings highlight the importance of improving our current methods of surveillance of ATP use in older adults in the outpatient setting.
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http://dx.doi.org/10.3390/ijerph17238707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727672PMC
November 2020

Quality of Care for Acute Kidney Disease: Current Knowledge Gaps and Future Directions.

Kidney Int Rep 2020 Oct 6;5(10):1634-1642. Epub 2020 Aug 6.

Section of Nephrology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.

Acute kidney injury (AKI) and acute kidney disease (AKD) are common complications in hospitalized patients and are associated with adverse outcomes. Although consensus guidelines have improved the care of patients with AKI and AKD, guidance regarding quality metrics in the care of patients after an episode of AKI or AKD is limited. For example, few patients receive follow-up laboratory testing of kidney function or post-AKI or AKD care through nephrology or other providers. Recently, the Acute Disease Quality Initiative developed a consensus statement regarding quality improvement goals for patients with AKI or AKD specifically highlighting efforts regarding quality and safety of care after hospital discharge after an episode of AKI or AKD. The goal is to use these measures to identify opportunities for improvement that will positively affect outcomes. We recommend that health care systems quantitate the proportion of patients who need and actually receive follow-up care after the index AKI or AKD hospitalization. The intensity and appropriateness of follow-up care should depend on patient characteristics, severity, duration, and course of AKI of AKD, and should evolve as evidence-based guidelines emerge. Quality indicators for discharged patients with dialysis requiring AKI or AKD should be distinct from end-stage renal disease measures. Besides, there should be specific quality indicators for those still requiring dialysis in the outpatient setting after AKI or AKD. Given the limited preexisting data guiding the care of patients after an episode of AKI or AKD, there is ample opportunity to establish quality measures and potentially improve patient care and outcomes. This review will provide specific evidence-based and expert opinion-based guidance for the care of patients with AKI or AKD after hospital discharge.
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http://dx.doi.org/10.1016/j.ekir.2020.07.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569680PMC
October 2020

AKI Treated with Renal Replacement Therapy in Critically Ill Patients with COVID-19.

J Am Soc Nephrol 2021 01 16;32(1):161-176. Epub 2020 Oct 16.

Division of Nephrology, Kings County Hospital Center, New York City Health and Hospital Corporation, Brooklyn, New York.

Background: AKI is a common sequela of coronavirus disease 2019 (COVID-19). However, few studies have focused on AKI treated with RRT (AKI-RRT).

Methods: We conducted a multicenter cohort study of 3099 critically ill adults with COVID-19 admitted to intensive care units (ICUs) at 67 hospitals across the United States. We used multivariable logistic regression to identify patient-and hospital-level risk factors for AKI-RRT and to examine risk factors for 28-day mortality among such patients.

Results: A total of 637 of 3099 patients (20.6%) developed AKI-RRT within 14 days of ICU admission, 350 of whom (54.9%) died within 28 days of ICU admission. Patient-level risk factors for AKI-RRT included CKD, men, non-White race, hypertension, diabetes mellitus, higher body mass index, higher d-dimer, and greater severity of hypoxemia on ICU admission. Predictors of 28-day mortality in patients with AKI-RRT were older age, severe oliguria, and admission to a hospital with fewer ICU beds or one with greater regional density of COVID-19. At the end of a median follow-up of 17 days (range, 1-123 days), 403 of the 637 patients (63.3%) with AKI-RRT had died, 216 (33.9%) were discharged, and 18 (2.8%) remained hospitalized. Of the 216 patients discharged, 73 (33.8%) remained RRT dependent at discharge, and 39 (18.1%) remained RRT dependent 60 days after ICU admission.

Conclusions: AKI-RRT is common among critically ill patients with COVID-19 and is associated with a hospital mortality rate of >60%. Among those who survive to discharge, one in three still depends on RRT at discharge, and one in six remains RRT dependent 60 days after ICU admission.
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http://dx.doi.org/10.1681/ASN.2020060897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894677PMC
January 2021

COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup.

Nat Rev Nephrol 2020 12 15;16(12):747-764. Epub 2020 Oct 15.

Division of Nephrology, Department of Medicine, University of Alabama, Birmingham, AL, USA.

Kidney involvement in patients with coronavirus disease 2019 (COVID-19) is common, and can range from the presence of proteinuria and haematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT; also known as kidney replacement therapy). COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and serves as an independent risk factor for all-cause in-hospital death in patients with COVID-19. The pathophysiology and mechanisms of AKI in patients with COVID-19 have not been fully elucidated and seem to be multifactorial, in keeping with the pathophysiology of AKI in other patients who are critically ill. Little is known about the prevention and management of COVID-19 AKI. The emergence of regional 'surges' in COVID-19 cases can limit hospital resources, including dialysis availability and supplies; thus, careful daily assessment of available resources is needed. In this Consensus Statement, the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI based on current literature. We also make recommendations for areas of future research, which are aimed at improving understanding of the underlying processes and improving outcomes for patients with COVID-19 AKI.
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http://dx.doi.org/10.1038/s41581-020-00356-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561246PMC
December 2020

Using best subset regression to identify clinical characteristics and biomarkers associated with sepsis-associated acute kidney injury.

Am J Physiol Renal Physiol 2020 12 12;319(6):F979-F987. Epub 2020 Oct 12.

Division of Nephrology, Department of Medicine, University of California, San Francisco, California.

Sepsis-associated acute kidney injury (AKI) is a complex clinical disorder associated with inflammation, endothelial dysfunction, and dysregulated coagulation. With standard regression methods, collinearity among biomarkers may lead to the exclusion of important biological pathways in a single final model. Best subset regression is an analytic technique that identifies statistically equivalent models, allowing for more robust evaluation of correlated variables. Our objective was to identify common clinical characteristics and biomarkers associated with sepsis-associated AKI. We enrolled 453 septic adults within 24 h of intensive care unit admission. Using best subset regression, we evaluated for associations using a range of models consisting of 1-38 predictors (composed of clinical risk factors and plasma and urine biomarkers) with AKI as the outcome [defined as a serum creatinine (SCr) increase of ≥0.3 mg/dL within 48 h or ≥1.5× baseline SCr within 7 days]. Two hundred ninety-seven patients had AKI. Five-variable models were found to be of optimal complexity, as the best subset of five- and six-variable models were statistically equivalent. Within the subset of five-variable models, 46 permutations of predictors were noted to be statistically equivalent. The most common predictors in this subset included diabetes, baseline SCr, angiopoetin-2, IL-8, soluble tumor necrosis factor receptor-1, and urine neutrophil gelatinase-associated lipocalin. The models had a c-statistic of ∼0.70 (95% confidence interval: 0.65-0.75). In conclusion, using best subset regression, we identified common clinical characteristics and biomarkers associated with sepsis-associated AKI. These variables may be especially relevant in the pathogenesis of sepsis-associated AKI.
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http://dx.doi.org/10.1152/ajprenal.00281.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792692PMC
December 2020

Biological Mechanisms of COVID-19 Acute Respiratory Distress Syndrome.

Am J Respir Crit Care Med 2020 12;202(11):1489-1491

Department of Medicine, and, Department of Anesthesia, University of California, San Francisco, San Francisco, California and.

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http://dx.doi.org/10.1164/rccm.202009-3629EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706166PMC
December 2020

Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells.

Am J Physiol Lung Cell Mol Physiol 2020 12 9;319(6):L908-L925. Epub 2020 Sep 9.

Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont.

Growing evidence demonstrates that human mesenchymal stromal cells (MSCs) modify their in vivo anti-inflammatory actions depending on the specific inflammatory environment encountered. Understanding this better is crucial to refine MSC-based cell therapies for lung and other diseases. Using acute exacerbations of cystic fibrosis (CF) lung disease as a model, the effects of ex vivo MSC exposure to clinical bronchoalveolar lavage fluid (BALF) samples, as a surrogate for the in vivo clinical lung environment, on MSC viability, gene expression, secreted cytokines, and mitochondrial function were compared with effects of BALF collected from healthy volunteers. CF BALF samples that cultured positive for (Asp) induced rapid MSC death, usually within several hours of exposure. Further analyses suggested the fungal toxin gliotoxin as a potential mediator contributing to CF BALF-induced MSC death. RNA sequencing analyses of MSCs exposed to either Asp+ or Asp- CF BALF samples identified a number of differentially expressed transcripts, including those involved in interferon signaling, antimicrobial gene expression, and cell death. Toxicity did not correlate with bacterial lung infections. These results suggest that the potential use of MSC-based cell therapies for CF or other lung diseases may not be warranted in the presence of .
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http://dx.doi.org/10.1152/ajplung.00218.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792680PMC
December 2020

Need for Additional Trials of Vitamin C for Sepsis.

JAMA 2020 08;324(6):607-608

University of California, San Francisco.

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http://dx.doi.org/10.1001/jama.2020.8633DOI Listing
August 2020

Recovery of Kidney Function Among Patients With Glomerular Disease Starting Maintenance Dialysis.

Am J Kidney Dis 2021 02 7;77(2):303-305. Epub 2020 Aug 7.

Division of Nephrology, Department of Medicine, University of California at San Francisco School of Medicine, San Francisco, CA; Department of Epidemiology and Biostatistics, University of California at San Francisco School of Medicine, San Francisco, CA; Division of Pediatric Nephrology, Department of Medicine, University of California at San Francisco School of Medicine, San Francisco, CA.

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http://dx.doi.org/10.1053/j.ajkd.2020.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016208PMC
February 2021

Association of patient weight status with plasma surfactant protein D, a biomarker of alveolar epithelial injury, in children with acute respiratory failure.

Pediatr Pulmonol 2020 10 7;55(10):2730-2736. Epub 2020 Aug 7.

Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.

Aims And Objectives: Alveolar epithelial injury is a key determinant of acute respiratory failure (ARF) severity. Plasma surfactant protein D (SP-D), a biomarker of alveolar epithelial injury, is lower in obese adults with ARF compared to their lean peers. We aimed to determine if children with ARF have similar variance in plasma SP-D associated with their weight status on admission.

Methods: Plasma SP-D was measured on days 0, 1, or 2 in children (1-18 years) with ARF enrolled in the genetic variation and biomarkers in children with acute lung injury and RESTORE studies. Weight classification (underweight, normal, overweight, and obese) was based on body mass index or weight-for-height z-scores. Associations between weight group and SP-D on each day were tested.

Results: Inclusion criteria were met in 212 subjects, 24% were obese. There were no differences among weight groups in SP-D levels on days 0 and 1. However, on day 2, there was a statistically significant linear trend for lower SP-D levels as weight increased in both the univariate analysis (P = .02) and when adjusting for age, ethnicity, and diagnosis of pediatric acute respiratory distress syndrome (P = .05).

Conclusions: Obesity was associated with lower plasma SP-D levels on day 2 of ARF. This finding may be explained by altered ARF pathogenesis in obese individuals or a reduced incidence of ventilator-induced lung injury.
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http://dx.doi.org/10.1002/ppul.24990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087214PMC
October 2020
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