The Association of Matrix Metalloproteinases With Acute Kidney Injury Following CPB-Supported Cardiac Surgery

Abstract

Background: Cardiac surgery–associated acute kidney injury (AKI) is an adverse outcome that increases morbidity and mortality in patients undergoing cardiac surgical procedures. To date, the use of serum creatinine levels as an early indicator of AKI has limitations because of its slow rise and poor predictive accuracy for renal injury. This delay in diagnosis may lead to prolonged initiation in treatment and increased risk for adverse outcomes. Objective: This pilot study explores serum and urine matrix metalloproteinases (MMPs)-2 and MMP-9 and their association, and potentially earlier detection of AKI in patients following cardiopulmonary bypass (CPB)–supported cardiac surgery. We hypothesize that increased activity of serum and urine levels MMP-2 and/ or MMP-9 are associated with AKI. Furthermore, MMP-2 and/ or MMP-9 may provide earlier identification of AKI as compared with serum levels of creatinine. Methods: During the study period, there were 150 CPB-supported surgeries, 21 of which developed AKI according to the Kidney Disease Improving Global Outcomes criteria. We then selected a sample of 21 matched cases from those patients who went through the surgery without developing AKI. Primary outcomes were the measurement via gel zymography of the serum and urine activity of MMP-2 and MMP-9 drawn at the following intervals: pre-CPB; 10-minute post-CPB; and 4-hour post-CPB time points. Secondary variables were the measurement of serum creatinine, intensive care unit (ICU) fluid balance, and length of ICU stay. Results: At the 10-minute and 4-hour post-CPB time points, the serum MMP-2 activity of AKI patients were significantly higher as compared with non-AKI patients ( P < .001 and P = .004), respectively. Similarly, at the 10-minute and 4-hour post-CPB time points, the serum MMP-9 activity of AKI patients was significantly higher as compared with non-AKI patients ( P = .001 and P = .014), respectively. The activity of urine MMP-2 and MMP-9 of AKI patients was significantly higher as compared with non-AKI patients at all 3 time points ( P = .004, P < .001, P < .001), respectively. Conclusion: Although the pilot study may have limitations, it has demonstrated that the serum and urine levels of activity of MMP-2 and MMP-9 are associated with the clinical endpoint of AKI and appear to have earlier rising levels as compared with those of serum creatinine. Furthermore, in depth, exploration is underway with a larger sample size to attempt validation of the analytical performance and reproducibility of the assay for MMP-2 and MMP-9 to aid in earlier diagnosis of AKI following CPB-supported cardiac surgery.

Metalloproteinases in Cardiac Surgery: A Systematic Review

“…A total of 20 relevant publications were retrieved for further assessment. Fifteen trials that enrolled a total of 431 participants met the inclusion criteria and were included in the systematic review [6,7,[11][12][13][14][15][16][17][18][19][20][21][22][23]. Two review authors (F.J., G.F.S.)…”

“…Furthermore, a high level of MMP-9 was linked to poor postoperative outcomes and was an independent risk factor for post-operative complications in 22 patients with constrictive pericarditis who underwent pericardiectomy with CPB [23]. Additionally, MMPs were discovered to be accurate biomarkers of acute kidney injury following CPB [22]. In 2008, a prospective randomized trial showed that aprotinin treatment decreased the blood levels of MMP-8 and MMP-9 during and six hours after CPB for the first time in humans [7].…”

“…A summary of the risk of biases of the included trials is reported in the Supplemental Data (Figures S2 and S3). Quality assessment for observational studies showed no high-quality studies, two medium-quality studies [15,21,22], and seven low-quality studies. Four out of five trials showed unclear random sequence generation.…”

“…Of the 15 studies included, 5 were prospective RCTs (n = 211) [6,7,16,18,19], and 1 was a retrospective observational study [23], whereas the remaining 9 were prospective observational NRCTs [11][12][13][14][15]17,[20][21][22]. All studies included patients submitted to cardiac surgery with CPB, but some better defined their population: seven studies enrolled patients undergoing CABG with CPB (n = 213) [7,[11][12][13][14]16,21], one study included patients submitted to off-pump or on-pump CABG [15], one enrolled patients submitted to pericardiectomy with CPB [23], and one included patients undergoing to CABG or valve replacement with CPB [6].…”

“…MMP levels were found to be significantly correlated with CPB in all included studies. MMP-9 levels were found to be increased after CPB start and during CPB [6,7,[11][12][13][14][15][16][17][18][19][20][21][22][23]. It is particularly overexpressed both in the myocardial tissue and circulating in the bloodstream [11,14].…”