Our results reveal that compared to ICU survivors, non-survivors had lower level of serum lipid, including HDL-C, TC, LDL-C and TG. Low serum HDL-C concentration is associated with increased hospital mortality of patients who are critically ill, presenting as an arc-shaped association with an inflection point at around 30 mg/dL. This pattern was also observed for patients with AKI. For septic patients, we observed a crude U-shaped association between HDL-C and hospital mortality. However, only low HDL-C significantly associated with increased hospital mortality. In addition, age, mechanical ventilation use, SOFA score and Elixhauser comorbidity score were strongly associated with a higher mortality rate in all groups.
First, we observed a significant drop in serum HDL-C,TC,LDL-C and TG concentration in non-survivors compared to survivors, which was also reported in several other studies(6, 17). This reduction could be explained by several hypothesis, including an acute over-consumption of HDL particles, a decrease in liver HDL synthesis, especially in case of hepatic failure, and/or an increased clearance following an upregulation of SRB1(18). For septic patients, redistribution of HDL particles from the intravascular to the extravascular compartment due to inflammation-induced capillary leakage(19),or replacement of ApoA-I from HDL particles by serum amyloid A (SAA) which accelerates its clearance all contribute to the reducing HDL-C levels (20, 21).
The correlation of HDL and mortality has not been analyzed in unselected critically ill ICU patients yet. There are several studies investing the relationship between HDL-C and mortality conducted among general population in recent years ,most of which revealed J-shaped or U-shaped relationship (3–5, 22, 23). For example, Zhong et al(3)’s research demonstrated that in the general population, HDL-C level is associated with all-cause mortality in a J-shaped dose-response manner with the lowest risk observed at HDL-C levels of 54–58 mg/dL ; both extremely high and low HDL-C levels are associated with an increased risk of mortality. Mazidi et al(4) reported both extremely low(≤ 30 mg/dL) and extremely high(≥ 100 mg/dL) HDL-C levels were associated with greater risk of mortalities among American adults. Our finding only demonstrated low HDL-C ‘s correlation to increased mortality rate. Several factors might have contributed to the differences between our finding and others. On one hand it largely arises from the physiological differences of critical and general population. On the other hand, it might result from the relative low level of HDL-C revealed in our study in critically ill ICU patients (maximal HDL-C is 92 mg/dL). There are limited studies on the correlation of HDL-C and mortality in critically ill patients except sepsis. Degoricija et al(24) reported low admission serum levels of HDL3-C are associated with an increased 3-month mortality in acute heart failure patients, whereas total HDL-C and HDL2-C showed no association. ZielinskiIt et al(25) reported that baseline HDL-C ≤ 46 mg/dl was independent predictors of 2-year mortality in elderly who underwent transcatheter aortic valve implantation (TAVI). Karatas et al(7) reported that serum HDL-C obtained within the first 24hours of hospital admission were independently reversely correlated with mortality in patients with acute pulmonary embolism. Zhang et al(8) reports decreased HDL-C (< 1.06 mmol/L) is an independent predictor for in-hospital mortality in acute pancreatitis. It is noticed that most studies revealed a negative effect of low HDL-C concentration on mortality, but due to the diversity of disease categories, sample size and research designs, the cut-off points may vary. In this case, the prognostic value of low HDL-C should be evaluated by clinicians in all critically ill patients.
For septic patients, the correlation between HDL-C and mortality was first reported by Chien et al(6). The low HDL cholesterol level < 20 mg/dL reported on day 1 was significantly associated with an increase in mortality and adverse clinical outcomes. Later, two studies reported low level of Apolipoprotein A-I, major constituent of HDL-C, were independent factors to predict mortality in sepsis(9, 17). Recently, Trinder et al(26) identified a rare missense variant in CETP (cholesteryl ester transfer protein gene; rs1800777-A) that was associated with significant reductions in HDL-C levels during sepsis, carriers of which had higher mortality rate compared with noncarriers, indicating a causal effect of reduced HDL levels on decreased sepsis survival. Our findings are in line with the above-mentioned studies, adding a powerful evidence due to its large sample size, demonstrating a protective role of HDL during courses of sepsis.
However, we also discovered an odd rise in mortality in the high HDL-C group though not significant. One explanation might be that some HDL particles become dysfunctional due to size modification and composition change during sepsis as reported in several studies which will lead to worsening outcomes (20, 27, 28). Due to the limitation of retrospective study, we are unable to further detect the function of HDL-C in our study. Future studies are needed to illustrate this problem.
For ICU patients with AKI, the impact of HDL-C on mortality has not been reported. In this study, we explored the association between HDL-C and adverse outcome of critically ill patients with AKI. Lower level HDL-C correlated with high hospital mortality rate, ICU mortality rate and longer ICU and hospital LOS. Our findings suggest that HDL-C might be a potential prognostic predictor of critically ill patients with AKI. However, we did not find a protective role of higher HDL-C level in avoiding adverse clinical outcomes. An observation study by Zwinger et al  also reported in patients with reduced kidney function, higher HDL-C did not associate with lower risk for mortality and there was interaction between HDL-C and estimated Glomerular Filtration Rate (eGFR) in predicting mortality. Although HDL-C confers its renal protection function during courses of AKI by different mechanisms(12), studies have shown patients with renal dysfunction have significant disturbances in HDL composition and function leading to impaired vasoprotective, antioxidative and anti-inflammatory properties (29–32). Further studies are needed to better characterize HDL dysfunction that is associated with renal dysfunction under acute physiologic stress to identify novel risk factors and therapeutic targets for AKI prevention and treatment in the future.
The advantage of the present study is the large sample size, which allowed for subgroup analysis and adjustment for confounding factors, but it also has limitations. Firstly, because this is a retrospective research, the association between HDL-C and mortality could only be inferred, further research is needed to establish a definitive causal link. Secondly, the serum concentration of HDL-C can be influenced by many cofounders, such as diabetes, liver function and kinds of drugs. However, due to the nature of retrospective study, these situations cannot be identified in this database. Finally, as mentioned in the materials and methods section, because it is difficult to obtain urine output information in MIMIC III, only the KDIGO criteria of creatinine was used to screen AKI patients in this study, which may lead to some AKI patients not being identified.