Our study strongly suggests that the incidence of postoperative AKI after liver resection is higher in patients with increasing ∆HVPG (at least ≥ 1mmHg) as compared to patients with unchanged ∆HVPG.
58% of patients with ∆HVPG ≥ 1mmHg developed AKI in contrast to only 22% of patients with stable ∆HVPG ≤0mmHg. The reported incidence of AKI in an unselected patient population undergoing noncardiac general surgery is approximately 10% and thus, considerably lower than in our study population [1]. Although the incidence of AKI did not differ significantly between both study groups, serum creatinine was significantly higher in patients with a ∆HVPG ≥ 1mmHg after surgery and their postoperative creatinine values remained significantly higher.
A retrospective analysis in over 38,000 patients undergoing noncardiac surgery showed that even minor increases in serum creatinine values are associated with a two-fold increased risk of death [1]. Our data highlight that patients undergoing liver resection are more likely to develop postoperative complications due to impaired renal function. Therefore, postoperative renal function should be closely monitored in these patient population.
Furthermore, optimal intraoperative fluid management is important to maintain perioperative renal function. Restrictive fluid therapy during abdominal surgery was associated with an increased risk of acute kidney injury compared to a liberal fluid regimen [13]. In our trial we performed esophagus doppler guided goal-directed fluid management to optimize intraoperative volume status and to minimize the risk of hypovolemia. All intraoperative hemodynamic parameters including MAP, stroke volume and cardiac output were similar between patients with increasing ∆HVPG ≥ 1mmHg and patients with stable ∆HVPG ≤0mmHg. A potential bias related to differences in intraoperative fluid management on the incidence of postoperative AKI can therefore be excluded.
Interestingly, a retrospective analysis of 167 patients undergoing living liver donor hepatectomy showed no effect of surgery on postoperative serum creatinine and BUN concentrations within the first three postoperative days [14]. This could be explained by apparent differences between both study populations, since we included patients scheduled for liver resection due to malignant liver disease who often suffered from preexisting comorbidities, while the aforementioned retrospective study only enrolled healthy middle-aged patients scheduled for liver donation. The abnormal liver parenchyma in patients with liver disease-associated liver cancer likely further enhance (postoperative) intrahepatic vascular resistance. The acute reduction of hepatic vascular bed due to liver resection results in increased hepatic vascular resistance and lead simultaneously to a reduction of hepatic vascular compliance [15]. The diseased liver parenchyma combined with acute perturbation of hepatoportal hemodynamics caused by surgery might be main trigger factors for an increase in postoperative HVPG. In patients with liver metastasis or cirrhosis, arterial hepatic blood flow was significantly higher as compared to healthy volunteers [16]. This might be a sign of decreased hepatic vascular compliance in malignant liver diseases. Therefore, it seems likely that reduced vascular compliance in these patients undergoing liver resection results in an increased postoperative HVPG which ultimately affects renal function.
A portal venous pressure exceeding 5 mmHg defines portal hypertension [17]. Although, the median increase in patients with increasing ∆HVPG was only 2 mmHg, the incidence of postoperative AKI was up to 58%. Patients undergoing liver resection due to malignant liver disease might, however, be more vulnerable to even small increases in HVPG, specifically when HVPG rises abruptly.
Increased portal venous pressure activate the hepatorenal reflex resulting in an impairment of renal physiology [18]. The activity of the SNS plays an important role in early and late hepatorenal disorders [19]. In patients with cirrhosis, increased plasma noradrenalin concentrations are common, which is explained by the enhanced SNS activity [20]. Interestingly, in our study only noradrenalin concentrations were significantly higher in patients with ∆HVPG ≥ 1mmHg as compared in patients with ∆HVPG ≤0mmHg. Adrenaline and dopamine were not affected by postoperative ∆HVPG. While several trials registered higher RAAS activity in patients with liver cirrhosis [21], we did not observe difference in RAAS activity between patients with increasing vs. stable postoperative HVPG. An potential explanation might be that the RAAS is more active in patients with long-standing cirrhosis with pronounced portal hypertension [22]. Consequently, RAAS specific biomarkers might be unable to assess the hepatorenal reflex in the immediate postoperative period. Noradrenalin on the other hand is released immediately from sympathetic nerve endings during stressful events and might therefore be more appropriate to assess the hepatorenal reflex and might further reflect systemic stress.
Preoperative estimation of functional liver reserve is important to predict postoperative liver failure in patients undergoing liver resection surgery [23, 24]. Low Platelet count, decreased cholinesterase and increased bilirubin are strong predictors for impaired liver recovery after surgery [23, 24]. Estimated liver function in patients with increasing ∆HVPG ≥ 1mmHg was significantly impaired and thus, these patients might be not able to compensate liver function after resection and counteract with an enhanced release of catecholamines, specifically noradrenalin. Noradrenaline is a strong alpha-receptor vasoconstrictor affecting renal blood flow [25]. Therefore, this could be another explanation for the higher incidence of AKI in patients with ∆HVPG ≥ 1mmHg.
A limitation of this trial is the small number of patients included and thus, the interpretation of our results has to be done with some caution. Although noradrenaline was significantly higher in patients with ∆HVPG ≥ 1mmHg, catecholamines have a short half-life of only a few minutes. Elevated concentrations in our study were measured during surgery and within 2 hours after surgery, therefor we cannot fully exclude the fact that this might be the stress response caused by surgery itself. In patients with ∆HVPG ≥ 1mmHg the resected liver volume was significantly larger than in the other group, and we unfortunately do not have information of long-term changes in ∆HVPG.
In conclusion, our data demonstrate that patients undergoing liver resection who show an immediate postoperative increase in HVPG are at considerable risk to develop postoperative AKI and therefore renal function should be monitored very closely. Due to our small sample size, our investigation should be seen as a hypothesis generating study. This emphasizes that further research is needed to clarify the effect of postoperative increases in HVPG on renal function.