Effect modification of dosing strategy (AUC or trough) on AKI associated with vancomycin in combination with piperacillin/tazobactam or cefepime and meropenem.

Piperacillin-tazobactam (TZP), cefepime (FEP), or meropenem (MEM) and vancomycin (VAN) are commonly used in combination for sepsis. Studies have shown an increased risk of acute kidney injury (AKI) with TZP and VAN compared to FEP or MEM. VAN guidelines recommend area under the curve (AUC) monitoring over trough (Tr) to minimize the risk of AKI. We investigated the association of AKI and MAKE-30 with the two VAN monitoring strategies when used in combination with TZP or FEP/MEM. Adult patients between 2015 and 2019 with VAN > 72 hours were included. Patients with AKI prior to or within 48 hours of VAN or baseline CrCl of ≤30 mL/min were excluded. Four cohorts were defined: FEP/MEM/Tr, FEP/MEM/AUC, TZP/Tr, and TZP/AUC. A Cox Proportional Hazard Model was used to model AKI as a function of the incidence rate of at-risk days, testing monitoring strategy as a treatment effect modification. Multivariable logistic regression was used to model MAKE-30. Overall incidence of AKI was 18.6%; FEP/MEM/Tr = 115 (14.6%), FEP/MEM/AUC = 52 (14.9%), TZP/Tr = 189 (26%), and TZP/AUC = 96 (17.1%) (P < 0.001). Both drug group [(TZP; P = 0.0085)] and monitoring strategy [(Tr; P = 0.0007)] were highly associated with the development of AKI; however, the effect was not modified with interaction term [(TZP*Tr); 0.085)]. The odds of developing MAKE-30 were not different between any group and FEP/MEM/AUC. The effect of VAN/TZP on the development of AKI was not modified by the VAN monitoring strategy (AUC vs trough). MAKE-30 outcomes were not different among the four cohorts.

Evaluation of Clinical and Machine Data of Critically Ill Adult COVID Patients with Acute Kidney Injury Exposed to Enhanced Hemoadsorption during CRRT.

INTRODUCTION: The FDA authorized the emergency use of enhanced hemoadsorption with oXiris in critically ill adult COVID patients with respiratory failure or severe disease to reduce inflammation. In this study, we evaluated critically ill adult COVID patients with acute kidney injury (AKI) who were exposed versus not exposed to enhanced hemoadsorption with oXiris during continuous renal replacement therapy (CRRT). METHODS: Retrospective cohort study of critically ill adult COVID patients with AKI requiring CRRT. Exposure to oXiris was defined as receiving oXiris for >12 cumulative hours and more than one-third of the time within the first 72 h of CRRT. Study outcomes included filter-specific performance metrics and clinical outcomes such as ventilator requirement, mortality, and dialysis dependence. Inverse probability treatment weighting was used to balance potential confounders in weighted regression models. RESULTS: 14,043 h of CRRT corresponding to 85 critically ill adult patients were analyzed. Among these, 2,736 h corresponded to oXiris exposure (n = 25 patients) and 11,307 h to a standard CRRT filter (n = 60 patients). Transmembrane pressures (TMPs) increased rapidly and were overall higher with oXiris versus standard filter, but filter life (median of 36.3 vs. 33.1 h, p = 0.913, respectively) and filter/clotting alarms remained similar in both groups. In adjusted models, oXiris exposure was not independently associated with the composite of hospital mortality and dialysis dependence at discharge (OR 2.13, 95% CI: 0.98-4.82, p = 0.06), but it was associated with fewer ventilator (ß = -15.02, 95% CI: -29.23 to -0.82, p = 0.04) and intensive care unit days (ß = -14.74, 95% CI: -28.54 to -0.95, p = 0.04) in survivors. DISCUSSION/CONCLUSION: In critically ill adult COVID patients with AKI requiring CRRT, oXiris filters exhibited higher levels of TMP when compared to a standard CRRT filter, but no differences in filter life and filter/clotting alarm profiles were observed. The use of oXiris was not associated with improvement in clinical outcomes such as hospital mortality or dialysis dependence at discharge.

Incidence and outcomes of acute kidney injury including hepatorenal syndrome in hospitalized patients with cirrhosis in the US.

BACKGROUND & AIMS: Acute kidney injury (AKI) in cirrhosis is common and associated with high morbidity, but the incidence rates of different etiologies of AKI are not well described in the US. We compared incidence rates, practice patterns, and outcomes across etiologies of AKI in cirrhosis. METHODS: We performed a retrospective cohort study of 11 hospital networks, including consecutive adult patients admitted with AKI and cirrhosis in 2019. The etiology of AKI was adjudicated based on pre-specified clinical definitions (prerenal/hypovolemic AKI, hepatorenal syndrome [HRS-AKI], acute tubular necrosis [ATN], other). RESULTS: A total of 2,063 patients were included (median age 62 [IQR 54-69] years, 38.3% female, median MELD-Na score 26 [19-31]). The most common etiology was prerenal AKI (44.3%), followed by ATN (30.4%) and HRS-AKI (12.1%); 6.0% had other AKI, and 7.2% could not be classified. In our cohort, 8.1% of patients received a liver transplant and 36.5% died by 90 days. The lowest rate of death was observed in patients with prerenal AKI (22.2%; p <0.001), while death rates were higher but not significantly different from each other in those with HRS-AKI and ATN (49.0% vs. 52.7%; p = 0.42). Using prerenal AKI as a reference, the adjusted subdistribution hazard ratio (sHR) for 90-day mortality was higher for HRS-AKI (sHR 2.78; 95% CI 2.18-3.54; p <0.001) and ATN (sHR 2.83; 95% CI 2.36-3.41; p <0.001). In adjusted analysis, higher AKI stage and lack of complete response to treatment were associated with an increased risk of 90-day mortality (p <0.001 for all). CONCLUSION: AKI is a severe complication of cirrhosis. HRS-AKI is uncommon and is associated with similar outcomes to ATN. The etiology of AKI, AKI stage/severity, and non-response to treatment were associated with mortality. Further optimization of vasoconstrictors for HRS-AKI and supportive therapies for ATN are needed. IMPACT AND IMPLICATIONS: Acute kidney injury (AKI) in cirrhosis carries high morbidity, and management is determined by the etiology of injury. However, a large and well-adjudicated multicenter database from US centers that uses updated AKI definitions is lacking. Our findings demonstrate that acute tubular necrosis and hepatorenal syndrome have similar outcomes (∼50% mortality at 90 days), though hepatorenal syndrome is uncommon (12% of all AKI cases). These findings represent practice patterns at US transplant/tertiary centers and can be used as a baseline, presenting the situation prior to the adoption of terlipressin in the US.

Prediction of Mortality and Major Adverse Kidney Events in Critically Ill Patients With Acute Kidney Injury.

RATIONALE & OBJECTIVE: Risk prediction tools for assisting acute kidney injury (AKI) management have focused on AKI onset but have infrequently addressed kidney recovery. We developed clinical models for risk stratification of mortality and major adverse kidney events (MAKE) in critically ill patients with incident AKI. STUDY DESIGN: Multicenter cohort study. SETTING & PARTICIPANTS: 9,587 adult patients admitted to heterogeneous intensive care units (ICUs; March 2009 to February 2017) who experienced AKI within the first 3 days of their ICU stays. PREDICTORS: Multimodal clinical data consisting of 71 features collected in the first 3 days of ICU stay. OUTCOMES: (1) Hospital mortality and (2) MAKE, defined as the composite of death during hospitalization or within 120 days of discharge, receipt of kidney replacement therapy in the last 48 hours of hospital stay, initiation of maintenance kidney replacement therapy within 120 days, or a ≥50% decrease in estimated glomerular filtration rate from baseline to 120 days from hospital discharge. ANALYTICAL APPROACH: Four machine-learning algorithms (logistic regression, random forest, support vector machine, and extreme gradient boosting) and the SHAP (Shapley Additive Explanations) framework were used for feature selection and interpretation. Model performance was evaluated by 10-fold cross-validation and external validation. RESULTS: One developed model including 15 features outperformed the SOFA (Sequential Organ Failure Assessment) score for the prediction of hospital mortality, with areas under the curve of 0.79 (95% CI, 0.79-0.80) and 0.71 (95% CI, 0.71-0.71) in the development cohort and 0.74 (95% CI, 0.73-0.74) and 0.71 (95% CI, 0.71-0.71) in the validation cohort (P < 0.001 for both). A second developed model including 14 features outperformed KDIGO (Kidney Disease: Improving Global Outcomes) AKI severity staging for the prediction of MAKE: 0.78 (95% CI, 0.78-0.78) versus 0.66 (95% CI, 0.66-0.66) in the development cohort and 0.73 (95% CI, 0.72-0.74) versus 0.67 (95% CI, 0.67-0.67) in the validation cohort (P < 0.001 for both). LIMITATIONS: The models are applicable only to critically ill adult patients with incident AKI within the first 3 days of an ICU stay. CONCLUSIONS: The reported clinical models exhibited better performance for mortality and kidney recovery prediction than standard scoring tools commonly used in critically ill patients with AKI in the ICU. Additional validation is needed to support the utility and implementation of these models. PLAIN-LANGUAGE SUMMARY: Acute kidney injury (AKI) occurs commonly in critically ill patients admitted to the intensive care unit (ICU) and is associated with high morbidity and mortality rates. Prediction of mortality and recovery after an episode of AKI may assist bedside decision making. In this report, we describe the development and validation of a clinical model using data from the first 3 days of an ICU stay to predict hospital mortality and major adverse kidney events occurring as long as 120 days after hospital discharge among critically ill adult patients who experienced AKI within the first 3 days of an ICU stay. The proposed clinical models exhibited good performance for outcome prediction and, if further validated, could enable risk stratification for timely interventions that promote kidney recovery.

The Optimization of Outpatient Hemodialysis Management for Acute Kidney Injury Requiring Dialysis Patients: A Quality Improvement Study.

INTRODUCTION: In 2017, the Centers for Medicare and Medicaid Services allowed survivors of hospitalized acute kidney injury requiring dialysis (AKI-D) who were ambulatory and still dependent on hemodialysis (HD) to receive treatment in outpatient dialysis facilities. This policy change generated the ongoing need to improve AKI-D care in the outpatient setting. METHODS: Quality improvement study in adult patients admitted to an outpatient HD unit with the diagnosis of AKI-D. We developed a protocol to manage these patients that included: (a) multidisciplinary evaluations; (b) personalized 3-tier HD prescription for dose/ultrafiltration rate and frequency; (c) weekly assessment of kidney recovery; and (d) patient empowerment. Patient- and protocol-specific characteristics were described. We analyzed hourly HD data and protocol adherence, and relevant hemodynamic data were compared according to HD-free survival at 90 days. RESULTS: A total of 457.3 h of HD from 9 patients under the AKI-D protocol were interrogated. Three out of 9 patients were alive and liberated from HD within the first 90 days of outpatient HD. Overall protocol adherence was 53.8% and did not differ by HD-free survival (54.5% vs. 53.7% in those that recovered vs. not). Protocol adherence was associated with fewer intradialytic hypotension events (peak to nadir blood pressure, p < 0.01), while intradialytic hypotension (pre- to post-blood pressure) occurred more frequently in patients who did not recover kidney function (p = 0.009). CONCLUSION: We demonstrated the feasibility of implementing a management protocol for AKI-D patients in an outpatient dialysis facility. We found that fewer episodes of intradialytic hypotension occurred when the outpatient HD management was adherent to the protocol. The feasibility of this protocol should be confirmed in other facilities, and importantly, efficacy testing to evaluate its impact on AKI-D outpatient care is necessary.

IL-17A Levels and Progression of Kidney Disease Following Hospitalization with and without Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) is associated with increased mortality and new or progressive chronic kidney disease (CKD). Inflammatory cells play an important role in acute organ injury. We previously demonstrated that serum IL-17A levels were significantly elevated in critically ill patients with AKI and independently associated with hospital mortality. We hypothesize that IL-17A levels are elevated in hospitalized patients with AKI at diagnosis, and sustained elevation after discharge is associated with subsequent CKD incidence or progression. METHODS: Observational convenience sampling study of hospital survivors of Stage 2 or 3 AKI and controls without AKI from the ASSESS-AKI study. Patients were classified as progression or non-progression based on a composite of CKD incidence, progression, or end-stage kidney disease. IL-17A levels were evaluated with S-Plex assay (MSD) at 0- (during hospitalization), 3- and 12-month post-discharge, and analyzed along with clinical and biomarker data up to 84 months following discharge. RESULTS: Among 171 AKI and 175 non-AKI participants, IL-17A levels were elevated in AKI vs. non-AKI patients at 0M, 3M and 12M timepoints (p<0.05 for all comparisons). Further, IL-17A levels were elevated in the progression vs. non-progression group at the 3- and 12-month timepoints for outcomes occurring at 3-6 months and 12-84 months, respectively (p<0.05 for both). In adjusted multivariable models, IL-17A levels were not independently associated with progression of kidney disease. IL-17A levels were positively correlated with kidney disease and immune activation biomarkers at all timepoints (p<0.001). CONCLUSIONS: IL-17A was higher in patients with AKI vs. without AKI during hospitalization and up to 1-year post-discharge. IL-17A was higher in patients with progression of kidney disease after hospitalization but not independently associated with subsequent progression of kidney disease in fully adjusted models.

Association of Phosphate-Containing versus Phosphate-Free Solutions on Ventilator Days in Patients Requiring Continuous Kidney Replacement Therapy.

BACKGROUND AND OBJECTIVES: Hypophosphatemia is commonly observed in patients receiving continuous KRT. Patients who develop hypophosphatemia may be at risk of respiratory and neuromuscular dysfunction and therefore subject to prolongation of ventilator support. We evaluated the association of phosphate-containing versus phosphate-free continuous KRT solutions with ventilator dependence in critically ill patients receiving continuous KRT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our study was a single-center, retrospective, pre-post cohort study of adult patients receiving continuous KRT and mechanical ventilation during their intensive care unit stay. Zero-inflated negative binomial regression with and without propensity score matching was used to model our primary outcome: ventilator-free days at 28 days. Intensive care unit and hospital lengths of stay as well as hospital mortality were analyzed with a t test or a chi-squared test, as appropriate. RESULTS: We identified 992 eligible patients, of whom 649 (65%) received phosphate-containing solutions and 343 (35%) received phosphate-free solutions. In multivariable models, patients receiving phosphate-containing continuous KRT solutions had 12% (95% confidence interval, 0.17 to 0.47) more ventilator-free days at 28 days. Patients exposed to phosphate-containing versus phosphate-free solutions had 17% (95% confidence interval, -0.08 to -0.30) fewer days in the intensive care unit and 20% (95% confidence interval, - 0.12 to -0.32) fewer days in the hospital. Concordant results were observed for ventilator-free days at 28 days in the propensity score matched analysis. There was no difference in hospital mortality between the groups. CONCLUSIONS: The use of phosphate-containing versus phosphate-free continuous KRT solutions was independently associated with fewer ventilator days and shorter stay in the intensive care unit.

Bone Quality and Fractures in Women With Osteoporosis Treated With Bisphosphonates for 1 to 14 Years.

Oral bisphosphonates are the primary medication for osteoporosis, but concerns exist regarding potential bone-quality changes or low-energy fractures. This cross-sectional study used artificial intelligence methods to analyze relationships among bisphosphonate treatment duration, a wide variety of bone-quality parameters, and low-energy fractures. Fourier transform infrared spectroscopy and histomorphometry quantified bone-quality parameters in 67 osteoporotic women treated with oral bisphosphonates for 1 to 14 years. Artificial intelligence methods established two models relating bisphosphonate treatment duration to bone-quality changes and to low-energy clinical fractures. The model relating bisphosphonate treatment duration to bone quality demonstrated optimal performance when treatment durations of 1 to 8 years were separated from treatment durations of 9 to 14 years. This may be due to a change in relationship of bone-quality parameters with treatment duration. This model also showed that the effects of bisphosphonate treatment duration were most highly correlated with changes in means and standard deviations of infrared spectroscopically derived mineral and matrix parameters and histomorphometric bone turnover parameters. A second model related treatment duration to bone fracture in all 22 patients who fractured while on treatment with bisphosphonates for more than 8 years. This second model showed that bisphosphonate treatment duration, not hip bone mineral density (BMD), was the most strongly correlated parameter to these low-energy bone fractures. Application of artificial intelligence enabled analysis of large quantities of structural, cellular, mineral, and matrix bone-quality parameters to determine relationships with long-term oral bisphosphonate treatment and fracture. Infrared spectroscopy provides clinically relevant bone-quality information of which bone mineral purity is among the most relevant. Nine or more years of bisphosphonate treatment was associated with abnormal bone mineral purity, matrix abnormalities, and low-energy fractures. These data justify limiting bisphosphonate treatment duration to 8 years. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Kidney Recovery in Patients With Acute Kidney Injury Treated in Outpatient Hemodialysis or Rehabilitation Facilities.

RATIONALE & OBJECTIVE: Since January 2017, patients with acute kidney injury requiring dialysis (AKI-D) can be discharged to outpatient dialysis centers for continued hemodialysis (HD) support. We aimed to examine the rate of kidney recovery, time to recovery, and hospitalization-related clinical parameters associated with kidney recovery in patients with AKI-D. STUDY DESIGN: Single-center prospective cohort study. SETTING & PARTICIPANTS: 111 adult patients who were admitted to the University of Kentucky Hospital, experienced AKI-D, and were discharged with need of outpatient HD. EXPOSURE: Hospitalization-related clinical parameters were evaluated. OUTCOME: Kidney recovery as a composite of being alive and no longer requiring HD or other form of kidney replacement therapy. ANALYTICAL APPROACH: Discrete-time survival analysis and logistic regression were used to determine adjusted probabilities of kidney recovery at prespecified time points and to evaluate clinical parameters associated with recovery. RESULTS: 45 (41%) patients recovered kidney function, 25 (55.5%) within the first 30 days following discharge, 16 (35.5%) within 30 to 60 days, and 4 (9%) within 60 to 90 days. Adjusted probabilities of recovery were 36.7%, 27.4%, and 6.3%, respectively. Of the remaining patients, 49 (44%) developed kidney failure requiring chronic kidney replacement therapy and 17 (15%) died or went to hospice. Patients who did not recover kidney function were older, had more comorbid conditions, had lower estimated glomerular filtration rates at baseline, and received more blood transfusions during hospitalization when compared with those who recovered kidney function. LIMITATIONS: Selection bias given that patients included in the study were all eligible for AKI management with outpatient HD as part of Medicare/Medicaid services. CONCLUSIONS: At least one-third of AKI-D survivors discharged from an acute care hospital dependent on HD recovered kidney function within the first 90 days of discharge, more commonly in the first 30 days postdischarge. Future studies should elucidate clinical parameters that can inform risk classification and interventions to promote kidney recovery in this vulnerable and growing population.