Effects of preoperative high-oral protein loading on short- and long-term renal outcomes following cardiac surgery: a cohort study.

BACKGROUND: Post-cardiac surgery acute kidney injury (AKI) is associated with increased mortality. A high-protein meal enhances the renal blood flow and glomerular filtration rate (GFR) and might protect the kidneys from acute ischemic insults. Hence, we assessed the effect of a preoperative high-oral protein load on post-cardiac surgery renal function and used experimental models to elucidate mechanisms by which protein might stimulate kidney-protective effects. METHODS: The prospective "Preoperative Renal Functional Reserve Predicts Risk of AKI after Cardiac Operation" study follow-up was extended to postoperative 12 months for 109 patients. A 1:2 ratio propensity score matching method was used to identify a control group (n = 214) to comparatively evaluate the effects of a preoperative protein load and standard care. The primary endpoints were AKI development and postoperative estimated GFR (eGFR) loss at 3 and 12 months. We also assessed the secretion of tissue inhibitor of metalloproteases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7), biomarkers implicated in mediating kidney-protective mechanisms in human kidney tubular cells that we exposed to varying protein concentrations. RESULTS: The AKI rate did not differ between the protein loading and control groups (13.6 vs. 12.3%; p = 0.5). However, the mean eGFR loss was lower in the former after 3 months (0.1 [95% CI - 1.4, - 1.7] vs. - 3.3 [95% CI - 4.4, - 2.2] ml/min/1.73 m2) and 12 months (- 2.7 [95% CI - 4.2, - 1.2] vs - 10.2 [95% CI - 11.3, - 9.1] ml/min/1.73 m2; p < 0.001 for both). On stratification based on AKI development, the eGFR loss after 12 months was also found to be lower in the former (- 8.0 [95% CI - 14.1, - 1.9] vs. - 18.6 [95% CI - 23.3, - 14.0] ml/min/1.73 m2; p = 0.008). A dose-response analysis of the protein treatment of the primary human proximal and distal tubule epithelial cells in culture showed significantly increased IGFBP7 and TIMP-2 expression. CONCLUSIONS: A preoperative high-oral protein load did not reduce AKI development but was associated with greater renal function preservation in patients with and without AKI at 12 months post-cardiac surgery. The potential mechanisms of action by which protein loading may induce a kidney-protective response might include cell cycle inhibition of renal tubular epithelial cells. Clinical trial registration ClinicalTrials.gov: NCT03102541 (retrospectively registered on April 5, 2017) and ClinicalTrials.gov: NCT03092947 (retrospectively registered on March 28, 2017).

Clinical and Operative Determinants of Acute Kidney Injury after Cardiac Surgery.

INTRODUCTION: Cardiac surgery-associated acute kidney injury (CSA-AKI) is associated with increased morbidity and mortality. OBJECTIVES: We aimed to identify potentially modifiable risk factors for CSA-AKI. METHODS: This was asingle-center retrospective cohort study of 495 adult patients undergoing cardiac surgery. AKI was diagnosed and staged using full KDIGO criteria incorporating baseline serum creatinine (SC) levels and correction of postoperative SC levels for fluid balance. We examined the association of routinely available clinical and laboratory data with AKI using multivariate logistic regression modeling. RESULTS: A total of 103 (20.8%) patients developed AKI: 16 (15.5%) patients were diagnosed with AKI upon hospital admission, and 87 (84.5%) patients were diagnosed with CSA-AKI. Correction of SC levels for fluid balance increased the number of AKI cases to 104 (21.0%), with 6 patients categorized to different AKI stages. Univariate logistic regression analysis identified five preoperative (age, sex, diabetes mellitus, preoperative systolic pulmonary arterial pressure [PSPAP], acute decompensated heart failure) and five intraoperative predictors of AKI (age, sex, red blood cell [RBC] volume transfused, use of minimally invasive surgery, duration of cardiopulmonary bypass). When all preoperative and intraoperative variables were incorporated into one model, six predictors remained significant (age, sex, use of minimally invasive surgery, RBC volume transfused, PSPAP, duration of cardiopulmonary bypass). Model discrimination performance showed an area under the curve of 0.69 for the model including only preoperative variables, 0.76 for the model including only intraoperative variables, and 0.77 for the model including all preoperative and intraoperative variables. CONCLUSIONS: Use of minimally invasive surgery and therapies mitigating PSPAP and intraoperative blood loss may offer protection against CSA-AKI.

Persistent decrease of renal functional reserve in patients after cardiac surgery-associated acute kidney injury despite clinical recovery.

Background: Cardiac surgery is a leading cause of acute kidney injury (AKI). Such AKI patients may develop progressive chronic kidney disease (CKD). Others, who appear to have sustained no permanent loss of function (normal serum creatinine), may still lose renal functional reserve (RFR). Methods: We extended the follow-up in the observational 'Preoperative RFR Predicts Risk of AKI after Cardiac Surgery' study from hospital discharge to 3 months after surgery for 86 (78.2%) patients with normal baseline estimated glomerular filtration rate (eGFR), and re-measured RFR with a high oral protein load. The primary study endpoint was change in RFR. Study registration at clinicaltrials.gov Identifier: NCT03092947, ISRCTN Registry: ISRCTN16109759. Results: At 3 months, three patients developed new CKD. All remaining patients continued to have a normal eGFR (93.3 ± 15.1 mL/min/1.73 m2). However, when stratified by post-operative AKI and cell cycle arrest (CCA) biomarkers, AKI patients displayed a significant decrease in RFR {from 14.4 [interquartile range (IQR) 9.5 - 24.3] to 9.1 (IQR 7.1 - 12.5) mL/min/1.73 m2; P < 0.001} and patients without AKI but with positive post-operative CCA biomarkers also experienced a similar decrease of RFR [from 26.7 (IQR 22.9 - 31.5) to 19.7 (IQR 15.8 - 22.8) mL/min/1.73 m2; P < 0.001]. In contrast, patients with neither clinical AKI nor positive biomarkers had no such decrease of RFR. Finally, of the three patients who developed new CKD, two sustained AKI and one had positive CCA biomarkers but without AKI. Conclusions: Among elective cardiac surgery patients, AKI or elevated post-operative CCA biomarkers were associated with decreased RFR at 3 months despite normalization of serum creatinine. Larger prospective studies to validate the use of RFR to assess renal recovery in combination with biochemical biomarkers are warranted.

Preoperative Renal Functional Reserve Predicts Risk of Acute Kidney Injury After Cardiac Operation.

BACKGROUND: Although acute kidney injury (AKI) frequently complicates cardiac operations, methods to determine AKI risk in patients without underlying kidney disease are lacking. Renal functional reserve (RFR) can be used to measure the capacity of the kidney to increase glomerular filtration rate under conditions of physiologic stress and may serve as a functional marker that assesses susceptibility to injury. We sought to determine whether preoperative RFR predicts postoperative AKI. METHODS: We enrolled 110 patients with normal resting glomerular filtration rates undergoing elective cardiac operation. Preoperative RFR was measured by using a high oral protein load test. The primary end point was the ability of preoperative RFR to predict AKI within 7 days of operation. Secondary end points included the ability of a risk prediction model, including demographic and comorbidity covariates, RFR, and intraoperative variables to predict AKI, and the ability of postoperative cell cycle arrest markers at various times to predict AKI. RESULTS: AKI occurred in 15 patients (13.6%). Preoperative RFR was lower in patients who experienced AKI (p < 0.001) and predicted AKI with an area under the receiver operating characteristic curve (AUC) of 0.83 (95% confidence interval [CI]: 0.70 to 0.96). Patients with preoperative RFRs not greater than 15 mL · min-1 · 1.73 m-2 were 11.8 times more likely to experience AKI (95% CI: 4.62 to 29.89 times, p < 0.001). In addition, immediate postoperative cell cycle arrest biomarkers predicted AKI with an AUC of 0.87. CONCLUSIONS: Among elective cardiac surgical patients with normal resting glomerular filtration rates, preoperative RFR was highly predictive of AKI. A reduced RFR appears to be a novel risk factor for AKI, and measurement of RFR preoperatively can identify patients who are likely to benefit from preventive measures or to select for use of biomarkers for early detection. Larger prospective studies to validate the use of RFR in strategies to prevent AKI are warranted. ClinicalTrials.gov identifier: NCT03092947, ISRCTN Registry: ISRCTN16109759.

Routine adoption of TIMP2 and IGFBP7 biomarkers in cardiac surgery for early identification of acute kidney injury.

BACKGROUND AND PURPOSE: Acute Kidney Injury (AKI) is a severe complication affecting many hospitalized patients after cardiac surgery, with negative impacts on short- and long-term clinical outcomes and on healthcare costs. Recently, clinical interest has been aimed at defining and classifying AKI, identifying risk factors and developing diagnostic strategies to identify patients at risk early on. Achieving an early and accurate diagnosis of AKI is a crucial issue, because prevention and timely detection may help to prevent negative clinical outcomes and avoid AKI-associated costs. In this retrospective study, we evaluate the NephroCheck Test as a diagnostic tool for early detection of AKI in a high-risk population of patients undergoing cardiac surgery at the San Bortolo Hospital of Vicenza. METHODS: We assessed the ability of the NephroCheck Test to predict the probability of developing CSA-AKI (cardiac surgery-associated AKI) and evaluated its accuracy as a diagnostic test, by building a multivariate logistic regression model for CSA-AKI prediction. RESULTS: Based on our findings, when the results of the NephroCheck Test are included in a multivariate model its performance is substantially improved, as compared to the benchmark model, which only accounts for the other clinical factors. We also define a rule - in terms of a probability cut-off - for discriminating cases that are at higher risk of developing AKI of any stage versus those in which AKI is less likely. CONCLUSIONS: Our study has implications in clinical practice: when a Nephrocheck Test result is >0.3 ng/dL, an automated electronic alert prompts the physician to intervene by following a checklist of preventive measures.