ACE inhibitors and angiotensin receptor blockers differentially alter the response to angiotensin II treatment in vasodilatory shock.

BACKGROUND: Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARB) medications are widely prescribed. We sought to assess how pre-admission use of these medications might impact the response to angiotensin-II treatment during vasodilatory shock. METHODS: In a post-hoc subgroup analysis of the randomized, placebo-controlled, Angiotensin Therapy for High Output Shock (ATHOS-3) trial, we compared patients with chronic angiotensin-converting enzyme inhibitor (ACEi) use, and patients with angiotensin receptor blocker (ARB) use, to patients without exposure to either ACEi or ARB. The primary outcome was mean arterial pressure after 1-h of treatment. Additional clinical outcomes included mean arterial pressure and norepinephrine equivalent dose requirements over time, and study-drug dose over time. Biological outcomes included baseline RAS biomarkers (renin, angiotensin-I, angiotensin-II, and angiotensin-I/angiotensin-II ratio), and the change in renin from 0 to 3 h. RESULTS: We included n = 321 patients, of whom, 270 were ACEi and ARB-unexposed, 29 were ACEi-exposed and 22 ARB-exposed. In ACEi/ARB-unexposed patients, angiotensin-treated patients, compared to placebo, had higher hour-1 mean arterial pressure (9.1 mmHg [95% CI 7.6-10.1], p < 0.0001), lower norepinephrine equivalent dose over 48-h (p = 0.0037), and lower study-drug dose over 48-h (p < 0.0001). ACEi-exposed patients treated with angiotensin-II showed similarly higher hour-1 mean arterial pressure compared to ACEi/ARB-unexposed (difference in treatment-effect: - 2.2 mmHg [95% CI - 7.0-2.6], pinteraction = 0.38), but a greater reduction in norepinephrine equivalent dose (pinteraction = 0.0031) and study-drug dose (pinteraction < 0.0001) over 48-h. In contrast, ARB-exposed patients showed an attenuated effect of angiotensin-II on hour-1 mean arterial pressure versus ACEi/ARB-unexposed (difference in treatment-effect: - 6.0 mmHg [95% CI - 11.5 to - 0.6], pinteraction = 0.0299), norepinephrine equivalent dose (pinteraction < 0.0001), and study-drug dose (pinteraction = 0.0008). Baseline renin levels and angiotensin-I/angiotensin-II ratios were highest in ACEi-exposed patients. Finally, angiotensin-II treatment reduced hour-3 renin in ACEi/ARB-unexposed and ACEi-exposed patients but not in ARB-exposed patients. CONCLUSIONS: In vasodilatory shock patients, the cardiovascular and biological RAS response to angiotensin-II differed based upon prior exposure to ACEi and ARB medications. ACEi-exposure was associated with increased angiotensin II responsiveness, whereas ARB-exposure was associated with decreased responsiveness. These findings have clinical implications for patient selection and dosage of angiotensin II in vasodilatory shock. Trial Registration ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

Anticoagulation practices for continuous renal replacement therapy: a survey of physicians from the United States.

BACKGROUND: During continuous renal replacement therapy (CRRT), anticoagulants are recommended for patients at low risk of bleeding and not already receiving systemic anticoagulants. Current anticoagulants used in CRRT in the US are systemic heparins or regional citrate. To better understand use of anticoagulants for CRRT in the US, we surveyed nephrologists and critical care medicine (CCM) specialists. METHODS: The survey contained 30 questions. Respondents were board certified and worked in intensive care units of academic medical centers or community hospitals. RESULTS: 150 physicians (70 nephrologists and 80 CCM) completed the survey. Mean number of CRRT machines in use increased ∼30% from the pre-pandemic era to 2022. Unfractionated heparin was the most used anticoagulant (43% of estimated patients) followed by citrate (28%). Respondents reported 29% of patients received no anticoagulant. Risk of hypocalcemia (52%) and citrate safety (42%) were the predominant reasons given for using no anticoagulant instead of citrate in heparin-intolerant patients. 84% said filter clogging was a problem when no anticoagulant was used, and almost 25% said increased transfusions were necessary. Respondents using heparin (n = 131) considered it inexpensive and easily obtainable, although of moderate safety, citing concerns of heparin-induced thrombocytopenia and bleeding. Anticoagulant citrate dextrose solution was the most used citrate. Respondents estimated that 37% of patients receiving citrate develop hypocalcemia and 17% citrate lock. CONCLUSIONS: Given the increased use of CRRT and the lack of approved, safe, and effective anticoagulant choices for CRRT in the US, effective use of current and other anticoagulant options needs to be evaluated.

Angiotensin II treatment is associated with improved oxygenation in ARDS patients with refractory vasodilatory shock.

BACKGROUND: The physiological effects of renin-angiotensin system modulation in acute respiratory distress syndrome (ARDS) remain controversial and have not been investigated in randomized trials. We sought to determine whether angiotensin-II treatment is associated with improved oxygenation in shock-associated ARDS. METHODS: Post-hoc subgroup analysis of the Angiotensin Therapy for High Output Shock (ATHOS-3) trial. We studied patients who met modified Berlin ARDS criteria at enrollment. The primary outcome was PaO2/FiO2-ratio (P:F) at 48-h adjusted for baseline P:F. Secondary outcomes included oxygenation index, ventilatory ratio, PEEP, minute-ventilation, hemodynamic measures, patients alive and ventilator-free by day-7, and mortality. RESULTS: Of 81 ARDS patients, 34 (42%) and 47 (58%) were randomized to angiotensin-II or placebo, respectively. In angiotensin-II patients, mean P:F increased from 155 mmHg (SD: 69) at baseline to 265 mmHg (SD: 160) at hour-48 compared with no change with placebo (148 mmHg (SD: 63) at baseline versus 164 mmHg (SD: 74) at hour-48)(baseline-adjusted difference: + 98.4 mmHg [95%CI 35.2-161.5], p = 0.0028). Similarly, oxygenation index decreased by - 6.0 cmH2O/mmHg at hour-48 with angiotensin-II versus - 0.4 cmH2O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH2O/mmHg, [95%CI - 8.6 to - 1.1], p = 0.0273). There was no difference in PEEP, minute ventilation, or ventilatory ratio. Twenty-two (64.7%) angiotensin-II patients had sustained hemodynamic response to treatment at hour-3 versus 17 (36.2%) placebo patients (absolute risk-difference: 28.5% [95%CI 6.5-47.0%], p = 0.0120). At day-7, 7/34 (20.6%) angiotensin-II patients were alive and ventilator-free versus 5/47(10.6%) placebo patients. Day-28 mortality was 55.9% in the angiotensin-II group versus 68.1% in the placebo group. CONCLUSIONS: In post-hoc analysis of the ATHOS-3 trial, angiotensin-II was associated with improved oxygenation versus placebo among patients with ARDS and catecholamine-refractory vasodilatory shock. These findings provide a physiologic rationale for trials of angiotensin-II as treatment for ARDS with vasodilatory shock. TRIAL REGISTRATION: ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

External validation of the modified sepsis renal angina index for prediction of severe acute kidney injury in children with septic shock.

BACKGROUND: Acute kidney injury (AKI) occurs commonly in pediatric septic shock and increases morbidity and mortality. Early identification of high-risk patients can facilitate targeted intervention to improve outcomes. We previously modified the renal angina index (RAI), a validated AKI prediction tool, to improve specificity in this population (sRAI). Here, we prospectively assess sRAI performance in a separate cohort. METHODS: A secondary analysis of a prospective, multicenter, observational study of children with septic shock admitted to the pediatric intensive care unit from 1/2019 to 12/2022. The primary outcome was severe AKI (≥ KDIGO Stage 2) on Day 3 (D3 severe AKI), and we compared predictive performance of the sRAI (calculated on Day 1) to the original RAI and serum creatinine elevation above baseline (D1 SCr > Baseline +). Original renal angina fulfillment (RAI +) was defined as RAI ≥ 8; sepsis renal angina fulfillment (sRAI +) was defined as RAI ≥ 20 or RAI 8 to < 20 with platelets < 150 × 103/µL. RESULTS: Among 363 patients, 79 (22%) developed D3 severe AKI. One hundred forty (39%) were sRAI + , 195 (54%) RAI + , and 253 (70%) D1 SCr > Baseline + . Compared to sRAI-, sRAI + had higher risk of D3 severe AKI (RR 8.9, 95%CI 5-16, p < 0.001), kidney replacement therapy (KRT) (RR 18, 95%CI 6.6-49, p < 0.001), and mortality (RR 2.5, 95%CI 1.2-5.5, p = 0.013). sRAI predicted D3 severe AKI with an AUROC of 0.86 (95%CI 0.82-0.90), with greater specificity (74%) than D1 SCr > Baseline (36%) and RAI + (58%). On multivariable regression, sRAI + retained associations with D3 severe AKI (aOR 4.5, 95%CI 2.0-10.2, p < 0.001) and need for KRT (aOR 5.6, 95%CI 1.5-21.5, p = 0.01). CONCLUSIONS: Prediction of severe AKI in pediatric septic shock is important to improve outcomes, allocate resources, and inform enrollment in clinical trials examining potential disease-modifying therapies. The sRAI affords more accurate and specific prediction than context-free SCr elevation or the original RAI in this population.

Performance of a Standardized Clinical Assay for Urinary C-C Motif Chemokine Ligand 14 (CCL14) for Persistent Severe Acute Kidney Injury.

Background: Clinical use of biomarkers requires the development of standardized assays and establishment of cutoffs. Urinary C-C motif chemokine ligand 14 (CCL14) has been validated to predict persistent severe AKI in critically ill patients with established AKI. We now report on the performance of standardized cutoffs using a clinical assay. Methods: A second aim of the multicenter RUBY Study was to establish two cutoffs for the prediction of persistent severe AKI (defined as KDIGO stage 3 AKI for at least 72 consecutive hours). Patients who received renal replacement therapy (RRT) or died before achieving 72 hours in stage 3 AKI were also considered to have reached the end point. Results: A cutoff value for urinary CCL14 of 1.3 ng/ml was determined to achieve high sensitivity (91%; 95% CI, 84% to 96%), and 13 ng/ml achieved high specificity (93%; 95% CI, 89% to 96%). The cutoff of 1.3 ng/ml identifies the majority (91%) of patients who developed persistent severe AKI with a negative predictive value of 92%. The cutoff at 13 ng/ml had a positive predictive value of 72% (with a negative predictive value of 75%). In multivariable adjusted analyses, a CCL14 concentration between 1.3 and 13 ng/ml had an adjusted odds ratio (aOR) of 3.82 (95% CI, 1.73 to 9.12; P=0.001) for the development of persistent severe AKI compared with those with a CCL14 ≤1.3 ng/ml, whereas a CCL14 >13 ng/ml had an aOR of 10.4 (95% CI, 3.89 to 29.9; P<0.001). Conclusions: Using a clinical assay, these standardized cutoffs (1.3 and 13 ng/ml) allow for the identification of patients at high risk for the development of persistent severe AKI. These results have immediate utility in helping to guide AKI patient care and may facilitate future clinical trials.Clinical Trial registry name and registration number: Identification and Validation of Biomarkers of Acute Kidney Injury Recovery, NCT01868724.

VASOPRESSOR-RESISTANT HYPOTENSION, COMBINATION VASOPRESSOR THERAPY, AND SHOCK PHENOTYPES IN CRITICALLY ILL ADULTS WITH VASODILATORY SHOCK.

ABSTRACT: Objective: To examine the risk factors, resource utilization, and 1-year mortality associated with vasopressor-resistant hypotension (VRH) compared with vasopressor-sensitive hypotension (VSH) among critically ill adults with vasodilatory shock. We also examined whether combination vasopressor therapy and patient phenotype were associated with mortality. Design: Retrospective cohort study. Setting: Eight medical-surgical intensive care units at the University of Pittsburgh Medical Center, Pittsburgh, PA. Patients : Critically ill patients with vasodilatory shock admitted between July 2000 and October 2008. Interventions : None. Measurements and Main Results: Vasopressor-resistant hypotension was defined as those requiring greater than 0.2 µg/kg per minute of norepinephrine equivalent dose of vasopressor consecutively for more than 6 h, and VSH was defined as patients requiring ≤0.2 µg/kg per minute to maintain MAP between 55 and 70 mm Hg after adequate fluid resuscitation. Of 5,313 patients with vasodilatory shock, 1,291 patients (24.3%) developed VRH. Compared with VSH, VRH was associated with increased risk of acute kidney injury (72.7% vs. 65.0%; P < 0.001), use of kidney replacement therapy (26.0% vs. 11.0%; P < 0.001), longer median (interquartile range [IQR]) intensive care unit length of stay (10 [IQR, 4.0-20.0] vs. 6 [IQR, 3.0-13.0] days; P < 0.001), and increased 1-year mortality (64.7% vs. 34.8%; P < 0.001). Vasopressor-resistant hypotension was associated with increased odds of risk-adjusted mortality (adjusted odds ratio [aOR], 2.93; 95% confidence interval [CI], 2.52-3.40; P < 0.001). When compared with monotherapy, combination vasopressor therapy with two (aOR, 0.91; 95% CI, 0.78-1.06) and three or more vasopressors was not associated with lower mortality (aOR, 0.93; 95% CI, 0.68-1.27). Using a finite mixture model, we identified four unique phenotypes of patient clusters that differed with respect to demographics, severity of illness, processes of care, vasopressor use, and outcomes. Conclusions: Among critically ill patients with vasodilatory shock, VRH compared with VSH is associated with increased resource utilization and long-term risk of death. However, combination vasopressor therapy was not associated with lower risk of death. We identified four unique phenotypes of patient clusters that require further validation.

Characterising acute kidney injury: The complementary roles of biomarkers of renal stress and renal function.

PURPOSE: Although epidemiological studies have enhanced our understanding of acute kidney injury, defining the biologic processes corresponding to the clinical phenotype remains challenging. We have examined biomarkers associated with renal stress plus markers of glomerular function to assess whether this approach may aid prediction of AKI or other relevant endpoints. MATERIALS & METHODS: Urinary [TIMP-2]·[IGFBP7], serum creatinine, plasma cystatin C and plasma proenkephalin 119-159 2 were analyzed in patients enrolled in the prospective, international, Sapphire study. Heterogenous critically ill patients (n = 723) were examined with a primary endpoint of development of KDIGO stage 2-3 within 12 h and a secondary endpoint of major adverse kidney events at 30 days (MAKE30). RESULTS: 100 patients (14%) reached the primary endpoint. Markers of renal stress outperformed those associated with glomerular function. Combining [TIMP-2]•[IGFBP7] with serum creatinine, but not the other functional markers, significantly (p = 0.02) increased the area under the ROC curve (AUC) from 0.80 (0.76-0.84) to 0.85 (0.81-0.89). In patients who did not develop AKI, all markers of glomerular filtration, but not [TIMP-2]·[IGFBP7], were significantly elevated in patients with a history of CKD (p < 0.05). CONCLUSIONS: The combination of cell-cycle arrest biomarkers, TIMP-2 and IGFBP7, with serum creatinine but not cystatin C or PENK improved risk stratification for the development of stage 2 or 3 AKI over [TIMP-2]·[IGFBP7] alone.

Utility of Biomarkers for Sepsis-Associated Acute Kidney Injury Staging.

Importance: The 23rd Acute Disease Quality Initiative (ADQI-23) consensus conference proposed a framework to integrate biomarkers into the staging of acute kidney injury (AKI). It is unknown whether tissue inhibitor of metalloproteinases 2 (TIMP-2) and insulinlike growth factor binding protein 7 (IGFBP7) could be used for staging. Objective: To test whether higher levels of urinary [TIMP-2] × [IGFBP7] are associated with lower survival among patients with the same functional stage of AKI. Design, Setting, and Participants: This cohort study was performed using data from the Protocolized Care for Early Septic Shock (ProCESS) trial, which enrolled critically ill patients with septic shock who presented at academic and community emergency departments and intensive care units in the US from March 2008 to May 2013. Patients with end-stage kidney disease, a reference serum creatinine level of 4 mg/dL or greater (to convert to µmol/L, multiply by 76.25), or missing data on serum creatinine levels or urinary levels of [TIMP-2] × [IGFBP7] were excluded. Data were analyzed from October 2020 to October 2021. Exposures: The presence of AKI, assessed using Kidney Disease: Improving Global Outcomes criteria within 24 hours after enrollment and the highest AKI stage as well as urinary [TIMP-2] × [IGFBP7] level at 6 hours after enrollment. A previously reported high-specificity cutoff level for [TIMP-2] × [IGFBP7] of 2.0 (ng/mL)2/1000 was used to categorize patients (including those without functional criteria of AKI) according to the new staging system proposed by the ADQI-23 as biomarker negative (urinary [TIMP-2] × [IGFBP7] level ≤2.0 [ng/mL]2/1000) or biomarker positive ([TIMP-2] × [IGFBP7] >2.0 [ng/mL]2/1000). Main Outcomes and Measures: Survival (assessed using Kaplan-Meier plots and the log-rank test) and mortality (assessed using relative risk [RR] 30 days after enrollment). Results: The analysis included 999 patients with a median age of 61 years (IQR, 50-73 years); 554 (55.5%) were male. Biomarker-positive patients had lower survival and higher mortality at 30 days in the groups with AKI stage 1 (RR, 2.20; 95% CI, 1.02-4.72), stage 2 (RR, 1.53; 95% CI, 1.04-2.27), and stage 3 (RR, 1.61; 95% CI, 1.00-2.60). The associations were specific to patients with AKI. No difference in 30-day survival was found between biomarker-positive and biomarker-negative patients in the absence of functional criteria for AKI (RR, 1.16; 95% CI, 0.45-3.01). Conclusions and Relevance: The findings suggest that assessment of the cell-cycle arrest biomarkers TIMP-2 and IGFBP7 may augment AKI staging for patients with functional criteria for AKI.

Permissive azotemia during acute kidney injury enables more rapid renal recovery and less renal fibrosis: a hypothesis and clinical development plan.

Preclinical models of acute kidney injury (AKI) consistently demonstrate that a uremic milieu enhances renal recovery and decreases kidney fibrosis. Similarly, significant decreases in monocyte/macrophage infiltration, complement levels, and other markers of inflammation in the injured kidney are observed across multiple studies and species. In essence, decreased renal clearance has the surprising and counterintuitive effect of being an effective treatment for AKI. In this Perspective, the author suggests a hypothesis describing why the uremic milieu is kidney protective and proposes a clinical trial of 'permissive azotemia' to improve renal recovery and long-term renal outcomes in critically ill patients with severe AKI.

Recalibration of the Renal Angina Index for Pediatric Septic Shock.

INTRODUCTION: Sepsis-associated acute kidney injury (AKI) is a common diagnosis in children that is associated with poor outcomes. The lack of therapeutic options once present makes early identification of at-risk patients essential. The renal angina index (RAI) has been previously validated to predict severe AKI in heterogeneous populations of critically ill children. The performance of this score specifically in children with septic shock is unknown. METHODS: A secondary analysis of a multicenter, prospective, observational study of 379 children with septic shock to determine the ability of the RAI to predict severe AKI at day 3, and to assess for the potential need for recalibration of the RAI in this unique subset of patients. RESULTS: At the original cutoff of ≥8, the RAI predicted day 3 severe AKI with an area under the receiving operating characteristic (AUROC) curve 0.90 (95% confidence interval [CI]: 0.86 to 93), 95% sensitivity, and 54% specificity. A Youden's index identified a higher optimal cutoff of ≥20 (sensitivity 83%, specificity 80%), and day 1 platelet count <150 × 103/µl was an independent predictor of severe AKI (adjusted odds ratio: 3.2; 95% CI: 1.7 to 6.3; P < 0.001). Recalibration of the RAI to include platelet count and this new threshold restored the sensitivity of the original ≥8 threshold (95%), while improving its specificity (69%). CONCLUSIONS: The RAI appears to be a sensitive and reliable tool for prediction of severe AKI in children with septic shock, although the use of a recalibrated sepsis-specific RAI using a higher cutoff and platelet count may be beneficial.

External validation of urinary C-C motif chemokine ligand 14 (CCL14) for prediction of persistent acute kidney injury.

BACKGROUND: Persistent acute kidney injury (AKI) portends worse clinical outcomes and remains a therapeutic challenge for clinicians. A recent study found that urinary C-C motif chemokine ligand 14 (CCL14) can predict the development of persistent AKI. We aimed to externally validate urinary CCL14 for the prediction of persistent AKI in critically ill patients. METHODS: This was a secondary analysis of the prospective multi-center SAPPHIRE study. We evaluated critically ill patients with cardiac and/or respiratory dysfunction who developed Kidney Disease: Improving Global Outcomes (KDIGO) stage 2-3 AKI within one week of enrollment. The main exposure was the urinary concentration of CCL14 measured at the onset of AKI stage 2-3. The primary endpoint was the development of persistent severe AKI, defined as ≥ 72 h of KDIGO stage 3 AKI or death or renal-replacement therapy (RRT) prior to 72 h. The secondary endpoint was a composite of RRT and/or death by 90 days. We used receiver operating characteristic (ROC) curve analysis to assess discriminative ability of urinary CCL14 for the development of persistent severe AKI and multivariate analysis to compare tertiles of urinary CCL14 and outcomes. RESULTS: We included 195 patients who developed KDIGO stage 2-3 AKI. Of these, 28 (14%) developed persistent severe AKI, of whom 15 had AKI ≥ 72 h, 12 received RRT and 1 died prior to ≥ 72 h of KDIGO stage 3 AKI. Persistent severe AKI was associated with chronic kidney disease, diabetes mellitus, higher non-renal APACHE III score, greater fluid balance, vasopressor use, and greater change in baseline serum creatinine. The AUC for urinary CCL14 to predict persistent severe AKI was 0.81 (95% CI, 0.72-0.89). The risk of persistent severe AKI increased with higher values of urinary CCL14. RRT and/or death at 90 days increased within tertiles of urinary CCL14 concentration. CONCLUSIONS: This secondary analysis externally validates urinary CCL14 to predict persistent severe AKI in critically ill patients.

The furosemide stress test: current use and future potential.

Loop diuretics are among the most widely used drugs worldwide and are commonly employed in the management of complications associated with acute kidney injury (AKI), namely volume overload and electrolyte management. The use of loop diuretics in critically ill patients with AKI is paramount to preventing or treating pulmonary edema. The naturetic response to a loop diuretic is based on its unique renal pharmacology. Our review article summarizes the pharmacology of furosemide in the intact nephron and discusses how this response might be altered by the presence of AKI. We discuss the increasing body of literature on the latest clinical utility of furosemide namely, it's challenge test, known as the furosemide stress test which has highlighted a new and novel role for furosemide over the past number of years. This test assists with the identification of AKI subjects at higher risk of AKI progression and the need for renal replacement therapy. The stress test can also predict cessation of continuous renal replacement therapy in patients with established AKI. On the basis of the evidence presented in this review, we propose future potential studies of furosemide in AKI.

Acute Kidney Disease to Chronic Kidney Disease.

Acute kidney injury (AKI) and chronic kidney disease are common interconnected syndromes that represent a public health problem. Acute kidney disease (AKD) is defined as the post-AKI status of acute or subacute kidney damage/dysfunction manifested by persistence of AKI beyond 7 to 90 days after the initial AKI diagnosis. Limited clinical data exist regarding AKD epidemiology but its incidence is observed in ∼25% of AKI survivors. Useful risk-stratification tools to predict risk of AKD and its prognosis are needed. Interventions on fluid management, nephrotoxic exposure, and follow-up care hold promise to ameliorate the burden of AKD and its complications.

Use of Biomarkers to Identify Acute Kidney Injury to Help Detect Sepsis in Patients With Infection.

OBJECTIVES: Although early recognition of sepsis is vital to improving outcomes, the diagnosis may be missed or delayed in many patients. Acute kidney injury is one of the most common organ failures in patients with sepsis but may not be apparent on presentation. Novel biomarkers for acute kidney injury might improve organ failure recognition and facilitate earlier sepsis care. DESIGN: Retrospective, international, Sapphire study. SETTING: Academic Medical Center. PATIENTS: Adults admitted to the ICU without evidence of acute kidney injury at time of enrollment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We stratified patients enrolled in the Sapphire study into three groups-those with a clinical diagnosis of sepsis (n = 216), those with infection without sepsis (n = 120), and those without infection (n = 387) at enrollment. We then examined 30-day mortality stratified by acute kidney injury within each group. Finally, we determined the operating characteristics for kidney stress markers (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) for prediction of acute kidney injury as a sepsis-defining organ failure in patients with infection without a clinical diagnosis of sepsis at enrollment. Combining all groups, 30-day mortality was 23% for patients who developed stage 2-3 acute kidney injury within the first 3 days compared with 14% without stage 2-3 acute kidney injury. However, this difference was greatest in the infection without sepsis group (34% vs 11%; odds ratio, 4.09; 95% CI, 1.53-11.12; p = 0.005). Using a (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) cutoff of 2.0 units, 14 patients (11.7%), in the infection/no sepsis group, tested positive of which 10 (71.4%) developed stage 2-3 acute kidney injury. The positive test result occurred a median of 19 hours (interquartile range, 0.8-34.0 hr) before acute kidney injury manifested by serum creatinine or urine output. Similar results were obtained using a cutoff of 1.0 for any stage of acute kidney injury. CONCLUSIONS: Use of the urinary (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) test could identify acute kidney injury in patients with infection, possibly helping to detect sepsis, nearly a day before acute kidney injury is apparent by clinical criteria.

Kinetic Changes of Plasma Renin Concentrations Predict Acute Kidney Injury in Cardiac Surgery Patients.

Rationale: The renin-angiotensin-aldosterone system is a major pathway in regulating blood pressure, glomerular filtration, and fluid homeostasis. During inflammatory diseases, generation of angiotensin II might be disturbed, leading to increased renin concentrations. Cardiac surgery and the use of cardiopulmonary bypass both induce inflammatory response and cardiovascular instability, which can contribute to acute kidney injury (AKI).Objectives: To investigate whether renin concentrations are associated with hypotension and AKI.Methods: This is a single-center, prospective, observational study among patients undergoing cardiac surgery.Measurements and Main Results: The primary endpoint was the occurrence of AKI within 72 hours after cardiac surgery. A total of 197 patients were available for the primary analysis. The median renin serum concentration was 40.2 µU/ml (quartile 1 [Q1]-Q3, 9.3-144.4) at baseline and 51.3 µU/ml (Q1-Q3, 19.1-167.0) 4 hours after cardiac surgery, whereas the difference between postoperation and preoperation concentrations (Δ-renin) was 3.7 µU/ml (Q1-Q3, -22.7 to 50.9). Patients with an elevated Δ-renin developed an AKI significantly more often (43% vs. 12.2%; P < 0.001). High Δ-renin after cardiac surgery was associated with a significantly lower mean arterial pressure, longer time on vasopressors, and longer length of ICU and hospital stay. The area under the curve (AUC) of Δ-renin for the prediction of AKI (AUC, 0.817; 95% confidence interval, 0.747-0.887) was significantly greater compared with the AUC of the postoperative renin concentrations (AUC, 0.702; 95% CI, 0.610-0.793; P = 0.007).Conclusions: Elevated renin concentrations were associated with cardiovascular instability and increased AKI after cardiac surgery. Elevated renin concentrations could be used to identify high-risk patients for cardiovascular instability and AKI who would benefit from timely intervention that could improve their outcomes.

Nephrologist Follow-Up Care of Patients With Acute Kidney Disease Improves Outcomes: Taiwan Experience.

OBJECTIVES: Acute kidney injury (AKI) and acute kidney disease (AKD) are a continuum on a disease spectrum and frequently progress to chronic kidney disease. Benefits of nephrologist subspecialty care during the AKD period after AKI are uncertain. METHODS: Patients with AKI requiring dialysis who subsequently became dialysis independent and survived for at least 90 days, defined as the AKD period, were identified from the Taiwanese population's health insurance database. Cox proportional hazard models using death as the competing risk before and after propensity-score matching were applied to evaluate various endpoints. RESULTS: Among a total of 20 260 patients with AKI requiring dialysis who became dialysis independent, only 7550 (37.3%) patients were followed up with by a nephrologist (F/Unephrol group) during the AKD period. During a mean 4.04 ± 3.56 years of follow-up, the patients in the F/Unephrol group were more often administered statin, antihypertensives, angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), diuretics, antiplatelet agents, and antidiabetic agents. The patients in the F/Unephrol group had a lower mortality rate (hazard ratio [HR] = 0.87, P < .001) and were less likely to have major adverse cardiovascular events (MACE) (subdistribution HR [sHR] = 0.85, P < .001), congestive heart failure (CHF) (sHR = 0.81, P < .001), and severe sepsis (sHR = 0.88, P = .008) according to the Cox proportional model after adjusting for mortality as a competing risk. During the AKD period, an increase in the frequency of nephrology visits was associated with improved outcomes. CONCLUSIONS: In this population-based cohort, even after weaning off acute dialysis, only a minority of patients visited a nephrologist during the AKD period. We showed that nephrology follow-up is associated with a decrease in MACE, CHF exacerbations, and sepsis, as well as lower mortality; thus it may improve outcomes in patients with AKD.

Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial.

Rationale: Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy.Objectives: To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS.Methods: We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours.Measurements and Main Results: Baseline serum renin concentration (normal range, 2.13-58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios (r = 0.39; P < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo (P < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88; P = 0.012) (P = 0.048 for the interaction).Conclusions: The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes.Clinical trial registered with www.clinicaltrials.gov (NCT02338843).

Serial Measurement of Cell-Cycle Arrest Biomarkers [TIMP-2] · [IGFBP7] and Risk for Progression to Death, Dialysis, or Severe Acute Kidney Injury in Patients with Septic Shock.

Rationale: Urinary TIMP-2 (tissue inhibitor of metalloproteinases-2) and IGFBP7 (insulin-like growth factor-binding protein 7) can predict acute kidney injury (AKI) in patients with sepsis.Objectives: To address critical questions about whether biomarkers can inform the response to treatment and whether they might be used to guide therapy, as most sepsis patients present with AKI.Methods: We measured [TIMP-2] · [IGFBP7] before and after a 6-hour resuscitation in 688 patients with septic shock enrolled in the ProCESS (Protocol-based Care for Early Septic Shock) trial. Our primary endpoint was stage 3 AKI, renal replacement therapy, or death within 7 days.Measurements and Main Results: The endpoint was reached in 113 patients (16.4%). In patients with negative [TIMP-2] · [IGFBP7] at baseline, those who became positive (>0.3 U) after resuscitation had three-times higher risk compared with those who remained negative (21.8% vs. 8.5%; P = 0.01; odds ratio [OR], 3.0; 95% confidence interval [CI], 1.31-6.87). Conversely, compared with patients with a positive biomarker at baseline that were still positive at Hour 6, risk was reduced for patients who became negative (23.8% vs. 9.8%; P = 0.01; OR, 2.15; 95% CI, 1.17-3.95). A positive [TIMP-2] · [IGFBP7] after resuscitation was associated with worse outcomes in both patients with and without AKI at that time point. The clinical response to resuscitation, as judged by the Acute Physiology and Chronic Health Evaluation II score, was weakly predictive of the endpoint (area under the curve, 0.68; 95% CI, 0.62-0.73) and improved with addition of [TIMP-2] · [IGFBP7] (0.72; 95% CI, 0.66-0.77; P = 0.03). Different resuscitation protocols did not alter biomarker trajectories, nor did they alter outcomes in biomarker-positive or biomarker-negative patients. However, biomarker trajectories were associated with outcomes.Conclusions: Changes in urinary [TIMP-2] · [IGFBP7] after initial fluid resuscitation identify patients with sepsis who have differing risk for progression of AKI.Clinical trial registered with www.clinicaltrials.gov (NCT00510835).

Sepsis-Associated Acute Kidney Disease.

INTRODUCTION: About one-third of critically ill patients with acute kidney injury (AKI) develop persistently decreased kidney function, known as acute kidney disease (AKD), which may progress to chronic kidney disease (CKD). Although sepsis is the most common cause of AKI, little is known about sepsis-associated AKD. METHODS: Using data from a large randomized trial including 1341 patients with septic shock, we studied patients with stage 2 or 3 AKI on day 1 of hospitalization. We defined AKD as a persistently reduced glomerular filtration rate for >7 days. In addition to clinical data, we measured several urinary biomarkers (tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 [TIMP-2∗IGFBP7], neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1], liver-type fatty acid binding protein, and type 4 collagen) at 0, 6, and 24 hours, to predict AKD. RESULTS: Of 598 patients, 119 (19.9%) died within 7 days, 318 (53.2%) had early reversal of AKI within the first 7 days, whereas 161 (26.9%) developed AKD. In patients with early reversal, 45 (14.2%) had relapsed AKI after early reversal, and only about one-third of these recovered. Among patients developing AKD, only 15 (9.3%) recovered renal function prior to discharge. Male sex, African American race, and underlying CKD were more predominant in patients developing AKD. None of the biomarkers tested performed well for prediction of AKD, although NGAL modestly increased the performance of a clinical model. CONCLUSIONS: AKD is common in patients with septic shock, especially among African American males and those with underlying CKD. Existing AKI biomarkers have limited utility for predicting AKD but might be useful together with clinical variables. Novel predictive biomarkers for renal recovery are needed.