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

Abstract

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).

Keywords: Acute kidney injury; Chronic kidney disease; Kidney stress test; Renal recovery.

Fig. 1

Changes in eGFR. eGFR by study day for patients receiving preoperative protein loading or standard preoperative care, change from preoperative values. p < 0.001 for the interaction day:group. Light grey: patients receiving standard preoperative care; dark grey: patients receiving preoperative high-oral protein load. The points are mean values with error bars, indicating the 95% confidence intervals. eGFR, estimated glomerular filtration rate

Fig. 2

eGFR among patients receiving a high-oral protein load compared to those receiving standard preoperative care. a eGFR at the time of admission as well at 3 and 12 months after surgery. b Change in eGFR relative to the time of admission. Light grey: patients receiving standard preoperative care; dark grey: patients receiving preoperative high-oral protein load. The points are mean values with error-bars, indicating the 95% confidence intervals. The number of patients at different time points for each group are provided in parentheses. eGFR, estimated glomerular filtration rate

Fig. 3

eGFR categorized on the basis of the occurrence of AKI and the AKI reversal status among patients receiving a preoperative high-oral protein load compared to those receiving standard preoperative care. a eGFR at the time of admission and at 3 and 12 months after surgery. b Changes in the eGFR relative to the time of admission. Light grey: patients with standard preoperative care; dark grey: patients receiving a preoperative high-oral protein load. The number of patients in each group at different time points are provided in parentheses. AKI, acute kidney injury; eGFR, estimated glomerular filtration rate

Fig. 4

Effect of dietary protein dose response treatment of primary human kidney tubule cells on the presence of TIMP-2 and IGFBP7 in the apical conditioned media. Isolated primary human proximal and distal tubule cells were subjected to dose–response analysis with whey protein, and secretion of the AKI biomarkers IGFBP7 and TIMP2 was assessed by immunoblot analysis of apical conditioned media. Densitometry values for (A) IGFBP7 from proximal tubule cells (4 genetically different samples) and (B) TIMP-2 from distal tubule cells (3 genetically different samples) were adjusted to protein concentration and normalized to no treatment. Asterisks indicate statistical significance from no treatment (p < 0.05). AKI, acute kidney injury; IGFBP7, insulin-like growth factor binding protein 7; TIMP-2, tissue inhibitor of metalloproteases-2