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Hepatocyte Growth Factor Mimetic ANG-3777 for Cardiac Surgery-Associated Acute Kidney Injury.

ABSTRACT: Introduction: Nearly one-third of patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB) experience cardiac surgery-associated (CSA) acute kidney injury (AKI); 5% require renal replacement therapy. ANG-3777 is a hepatocyte growth factor mimetic. In vitro, ANG-3777 reduces apoptosis and increases cell proliferation, migration, morphogenesis, and angiogenesis in injured kidneys. In animal models, ANG-3777 mitigates the effects of renal damage secondary to ischemia reperfusion injury and nephrotoxic chemicals. Phase 2 data in AKI of renal transplantation have shown improved renal function and comparable safety relative to placebo. The Guard Against Renal Damage (GUARD) study is a phase 2 proof of concept trial of ANG-3777 in CSA-AKI.

Methods: GUARD is a 240-patient, multicenter, double-blind, randomized placebo-controlled trial to assess the efficacy and safety of ANG-3777 in patients at elevated pre-surgery risk for AKI undergoing coronary artery bypass graft (CABG) or heart valve repair/replacement requiring CPB. Subjects are randomized 1:1 to receive ANG-3777 (2 mg/kg) or placebo. Study drug is dosed via 4 daily intravenous 30-minute infusions. The first dose is administered less than 4 hours after completing CPB, second at 24 ± 2 hours post-CPB, with two subsequent doses at 24 ± 2 hours after the previous dose.

Results: The primary efficacy endpoint is percent change from baseline serum creatinine to mean area under the curve from days 2 through 6. Secondary endpoints include change in estimated glomerular filtration rate from baseline to day 30, the proportion of patients diagnosed with AKI by stage through day 5, and the length of CSA-AKI hospitalization. Safety will include adverse events and laboratory measures.

Conclusion: This phase 2 study of ANG-3777 provides data to develop a phase 3 registrational study in this medically complex condition.

SUBMITTER: Ayad S

PROVIDER: S-EPMC7710816 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Hepatocyte Growth Factor Mimetic ANG-3777 for Cardiac Surgery-Associated Acute Kidney Injury.

Ayad Sabry S Neylan John F JF Mayne Tracy J TJ Gouveia Deborah D Swaminathan Madhav M

Kidney international reports 20200925 12

<h4>Introduction</h4>Nearly one-third of patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB) experience cardiac surgery-associated (CSA) acute kidney injury (AKI); 5% require renal replacement therapy. ANG-3777 is a hepatocyte growth factor mimetic. <i>In vitro,</i> ANG-3777 reduces apoptosis and increases cell proliferation, migration, morphogenesis, and angiogenesis in injured kidneys. In animal models, ANG-3777 mitigates the effects of renal damage secondary to ischemia ...[more]

PMID: 33305126

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Project description:Growth-differentiation factor-15 (GDF-15) is an emerging humoral marker for risk stratification in cardiovascular disease. Cardiac-surgery-associated acute kidney injury (CSA-AKI), an important complication in patients undergoing cardiac surgery, is associated with poor prognosis. The present secondary analysis of an observational cohort study aimed to determine the role of GDF-15 in predicting CSA-AKI compared with the Cleveland-Clinic Acute Renal Failure (CC-ARF) score and a logistic regression model including variables associated with renal dysfunction.Preoperative plasma GDF-15 was determined in 1176 consecutive patients undergoing elective cardiac surgery. Patients with chronic kidney disease stage 5 were excluded. AKI was defined according to Kidney-Disease-Improving-Global-Outcomes (KDIGO) - creatinine criteria. The following variables were screened for association with development of postoperative AKI: age, gender, additive Euroscore, serum creatinine, duration of cardiopulmonary bypass, duration of surgery, type of surgery, total circulatory arrest, preoperative hemoglobin, preoperative oxygen-supplemented cerebral oxygen saturation, diabetes mellitus, hemofiltration during ECC, plasma GDF-15, high sensitivity troponin T (hsTNT), and N-terminal prohormone of B-type natriuretic peptide (NTproBNP).There were 258 patients (21.9 %) with AKI (AKI stage 1 (AKI-1), n?=?175 (14.9 %); AKI-2, n?=?6 (0.5 %); AKI-3, n?=?77 (6.5 %)). The incidence of AKI-1 and AKI-3 increased significantly from the lowest to the highest tertiles of GDF-15. In logistic regression, preoperative GDF-15, additive Euroscore, age, plasma creatinine, diabetes mellitus, and duration of cardiopulmonary bypass were independently associated with AKI. Inclusion of GDF-15 in a logistic regression model comprising these variables significantly increased the area under the curve (AUC 0.738 without and 0.750 with GDF-15 included) and the net reclassification ability to predict AKI. Comparably, in receiver operating characteristic analysis the predictive capacity of the CC-ARF score (AUC 0.628) was improved by adding GDF-15 (AUC 0.684) but this score also had lower predictability than the logistic regression model. In random forest analyses the predictive capacity of GDF-15 was especially pronounced in patients with normal plasma creatinine.This suggests that preoperative plasma GDF-15 independently predicts postoperative AKI in patients undergoing elective cardiac surgery and is particularly helpful for risk stratification in patients with normal creatinine.NCT01166360 on July 20, 2010.

Dataset Information

Hepatocyte Growth Factor Mimetic ANG-3777 for Cardiac Surgery-Associated Acute Kidney Injury.

Publications

Hepatocyte Growth Factor Mimetic ANG-3777 for Cardiac Surgery-Associated Acute Kidney Injury.

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