Hemolysis and Acute Kidney Injury Following Cardiac Surgery With Cardiopulmonary Bypass in Patients With Preexisting Renal Dysfunction

Acute kidney injury (AKI) is a frequent and serious complication following cardiac surgery with cardiopulmonary bypass (CPB), particularly in patients with preexisting renal dysfunction. In this study by Volleman et al., researchers investigated the relationship between CPB-induced hemolysis, endothelial damage, and the development of postoperative AKI in a high-risk population. Specifically, the study focused on whether cell-free hemoglobin (CFHb), a marker of hemolysis, could serve as a predictive biomarker for AKI. 

The study was conducted as a substudy of a randomized controlled trial and included 89 adult patients undergoing cardiac surgery with CPB who had impaired renal function prior to surgery. The cohort was high-risk, defined by reduced estimated glomerular filtration rate (eGFR) or the presence of diabetes with moderate renal impairment. Among these patients, 21% developed postoperative AKI, highlighting the clinical significance of this complication in vulnerable populations.

Cardiopulmonary bypass exposes blood to non-physiological mechanical forces, leading to hemolysis. This process results in the release of CFHb, which can promote oxidative stress, nitric oxide scavenging, and endothelial dysfunction. As described on page 2, these mechanisms contribute to impaired microcirculation and tissue oxygenation, potentially increasing the risk of kidney injury. The kidneys are particularly susceptible because they play a central role in clearing CFHb, exposing renal tubular cells to toxic effects. 

The study found that CFHb levels significantly increased after surgery, peaking within one hour of ICU admission (22.5 vs. 5.4 mg/dL, p < 0.001). This is visually supported by the graph on page 5 (Figure 1A), which shows a sharp postoperative rise in CFHb levels. Lactate dehydrogenase (LDH), another marker of hemolysis, also increased and continued to rise for up to 48 hours. Meanwhile, haptoglobin levels decreased, indicating consumption during hemoglobin binding. These findings confirm that CPB induces measurable hemolysis. 

Importantly, patients who developed AKI had higher postoperative CFHb and LDH levels compared to those who did not, suggesting a potential association between hemolysis and kidney injury. However, when evaluated using logistic regression models, CFHb did not independently predict AKI. As shown in the ROC curve on page 6 (Figure 4), adding CFHb to a baseline clinical model (including diabetes, transfusion, and baseline creatinine) did not significantly improve predictive performance (AUC 0.80 vs. 0.83, p > 0.3). 

The study also explored markers of inflammation and endothelial damage. Tumor necrosis factor-alpha (TNF-α) and intercellular adhesion molecule-1 (ICAM-1) increased postoperatively, indicating systemic inflammation. Angiopoietin-2, a marker of endothelial injury, rose progressively and was higher in patients who developed AKI at 24 hours. The boxplot on page 5 (Figure 2D) illustrates this difference. However, angiopoietin-2 was not independently associated with AKI after adjusting for repeated measures, and CFHb levels were not correlated with angiopoietin-2 levels. 

Markers of kidney injury showed stronger predictive value. As shown in Figure 3 on page 6, serum creatinine, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) all increased significantly in patients who developed AKI. NGAL, in particular, rose early and demonstrated strong predictive capability, suggesting it may be a more clinically useful biomarker than CFHb. 

The findings challenge the assumption that hemolysis is a primary driver of AKI in patients with preexisting renal dysfunction. While hemolysis clearly occurs during CPB and is more pronounced in patients who develop AKI, its incremental contribution to risk prediction appears limited. As discussed on page 7, baseline renal impairment may overshadow the effects of hemolysis, making traditional risk factors such as preoperative creatinine more important predictors. 

This study has several strengths, including its focus on a high-risk population often underrepresented in prior research and its use of detailed biomarker analysis. However, limitations include a relatively small sample size and limited statistical power, as well as the absence of intraoperative plasma measurements immediately after CPB.

In conclusion, this study demonstrates that while CPB-induced hemolysis and endothelial activation are present in patients with preexisting renal dysfunction, CFHb does not serve as a reliable independent predictor of postoperative AKI. These findings suggest that future research should focus on alternative biomarkers and mechanisms, as well as targeted strategies to reduce kidney injury in this vulnerable population.