Low HDL-C can be a biomarker to predict persistent severe AKI in septic patients? A retrospective cohort study

Acute kidney injury (AKI) is a highly prevalent disease worldwide, with sepsis being the most common factor leading to AKI in critically ill patients, accounting for 40% of cases [1]. A recent study estimated that 68% of sepsis patients have AKI upon admission, with severe AKI occurring in 40% of cases and subsequent kidney replacement therapy (KRT) being required during their stay in the intensive care unit (ICU) for 27% of them [2]. The development of sepsis-related AKI is associated with higher mortality rates and longer hospital stays [3].

In clinical practice, the identification of persistent AKI is of great clinical significance. Firstly, the duration of AKI is closely related to patient prognosis and the risk of end-stage renal failure. Recent evidence has shown that two-thirds of AKI patients recover kidney function within 3–7 days, while those with persistent AKI have significantly lower one-year survival rates [4]. Additionally, the persistence of AKI also increases the risk of developing chronic kidney disease (CKD) in individuals [5]. Early identification and active intervention in individuals at risk for persistent AKI can potentially impact its progression to CKD [5, 6]. Secondly, the duration of AKI is closely associated with the need for kidney replacement therapy (KRT). Studies have indicated that some patients may benefit from starting KRT earlier, while others may not require such treatment as they quickly regain kidney function [7]. Therefore, predicting short-term reversibility of AKI may help assess the likelihood of needing KRT and ultimately determine the optimal timing to initiate it. Given the importance of identifying persistent renal injury, new tools including urinary biomarkers and renal Doppler ultrasound have recently been evaluated for this purpose [8, 9].

High-density lipoprotein (HDL) possesses anti-inflammatory, antioxidant, and endothelial repair-promoting properties, participating in the regulation of various pathological processes that influence the progression of sepsis associated acute kidney injury (SA-AKI). HDL increases liver clearance of LPS through scavenger receptor class B type 1 (SR-B1) [10], thereby alleviating LPS-TLR-4-mediated renal tubular injury [11]. HDL may also affect the development of AKI during sepsis by directly and indirectly inhibiting inflammatory responses. HDL can also suppress inflammation during sepsis by inducing the expression of transcription factor 3, reducing the production of IL-6 and TNF-a in macrophages [12‐18]. In addition, HDL can protect endothelial function by inhibiting the expression of intercellular adhesion molecule 1(ICAM-1) and stimulating endothelial nitric oxide synthase (eNOS) activity [19, 20]. The use of Apo A-I mimetic peptide, a major component of HDL structure, is associated with improved renal function in septic animal models [21]. In population studies, it has been found that low levels of high-density lipoprotein during sepsis are associated with an increased risk of sepsis-associated AKI and subsequent decrease in estimated glomerular filtration rate(eGFR) [22]. These results indicate that high-density lipoprotein may be a marker of kidney injury during sepsis, but the correlation between low HDL-C and persistent renal dysfunction is still unknown.

The purpose of this study is to determine whether plasma HDL-C measured within 24 h after admission to the ICU can predict persistent severe acute kidney injury and KRT. The secondary objective is to evaluate the potential use of HDL-C in combination with routine clinical data.

The plasma HDL-C levels of patients with persistent severe SA-AKI within 24 h after admission to the ICU were significantly lower than those of patients with non-persistent severe AKI. However, HDL-C showed poor discrimination between persistent severe SA-AKI and non-persistent severe SA-AKI, and did not improve the predictive performance of the clinical model. Our study results do not support the use of plasma HDL-C levels within 24 h after admission to the ICU for identifying persistent severe SA-AKI.

In clinical practice, early identification of persistent severe SA-AKI is of great clinical significance. Early recognition of individuals at risk for persistent AKI and proactive intervention and management can potentially impact the progression of AKI to CKD [5]. Additionally, predicting the short-term reversibility of AKI may help assess the likelihood of needing KRT and ultimately determine the optimal timing to initiate KRT [7]. Previous studies have focused on early identification of persistent renal injury using biomarkers, renal ultrasound, and clinical prediction models [8, 9, 28‐30]. Although conflicting results exist in these studies, some progress has been made in early identification of persistent SA-AKI through biomarker-based approaches [29]. Therefore, further exploration into identifying subtypes of SA-AKI based on biomarkers remains an area worth investigating.

High-density lipoprotein (HDL) can stimulate the activity of eNOS through SR-B1, and eNOS is involved in regulating the pathological process that affects the progression of SA-AKI. During sepsis, decreased eNOS activity can lead to microcirculatory dysfunction, which may result in local renal ischemia and contribute to kidney damage and the development of SA-AKI [20]. In a small study involving kidney transplant patients, it was found that among 7 patients with persistent AKI, 6 had reduced eNOS activity in peritubular capillaries isolated from renal biopsy samples. However, among 16 patients with rapid recovery from AKI, only 6 had reduced eNOS activity [31]. This study suggests a correlation between eNOS and the duration of AKI. Another previous study [22] found that compared to patients with normal or high concentrations, those with low HDL-C levels during early sepsis had a 2.8-fold increased risk of developing SA-AKI. Furthermore, HDL-C concentration predicted stages 2–3 SA-AKI with an AUC of 0.754. Although this study did not evaluate the diagnostic performance of HDL-C for diagnosing persistent severe SA-AKI, it did find an independent association between low HDL-C concentration during early sepsis and long-term decline in glomerular filtration rate (adjusted for risk factors including hypertension and diabetes). Based on these findings, we hypothesized that blood HDL-C levels could serve as biomarkers for predicting persistent SA-AKI. However, our research results do not support this hypothesis. We found that plasma HDL-C levels measured within 24 h after ICU admission had an AUC (95% CI) of 0.621 (0.56–0.69) for predicting persistent severe SA-AKI, with a best cutoff value of 31.5 mg/dl, sensitivity of 74%, specificity of 46%. HDL-C was not independently associated with persistent severe SA-AKI and did not improve the predictive performance of the clinical model. Considering the close association between persistent severe SA-AKI and kidney replacement therapy (KRT), we further evaluated the predictive value of blood HDL-C for KRT treatment. Similarly, low HDL-C was not independently associated with KRT and had relatively low clinical efficacy in predicting KRT outcomes.

The HDL-C levels are associated with poor prognosis in sepsis patients. Research has found that during the early stage of sepsis, HDL-C concentration rapidly decreases and whether it recovers or continues to decline affects the survival status of sepsis [32]. In a small-scale study, when the HDL concentration at hospital admission was less than 20 mg/dL, the sensitivity and specificity for predicting 30-day mortality rate were 80% [33]. Transient and persistent SA-AKI may have similar pathophysiological mechanisms [34], and some believe that reversibility of AKI is more related to the severity of kidney damage rather than its mechanism [35]. Our study also found that the SOFA score and APSIIIscore were significantly higher in the persistent SA-AKI group compared to non-persistent severe SA-AKI group, while HDL-C concentration showed a significant negative correlation with severity scores. However, even so, HDL-C still has low predictive efficacy for diagnosing persistent severe SA-AKI.

However, it should be noted that our study only focused on the static value of HDL-C within 24 h after admission to the ICU. This result suggests that HDL-C within 24 h of ICU admission is not very effective in predicting persistent severe SA-AKI. However, our study and previous clinical research results suggest a negative correlation between HDL-C and serum creatinine levels as well as severity scores, and low HDL-C is associated with long-term decline in glomerular filtration rate [22]. These results still indicate that HDL-C may have potential value in predicting persistent AKI, similar to changes in creatinine values. Paying attention to the trend of HDL-C over time may improve the diagnostic value for predicting persistent SA-AKI. However, this study is a retrospective study based on a database and did not collect dynamic changes in HDL-C data. Therefore, further prospective studies are needed to validate the diagnostic value of HDL-C changes for persistent severe SA-AKI. In addition, we excluded 112 patients who had missing plasma creatinine and urine output measurements at 72 h after diagnosis of SA-AKI. This may imply that these patients' renal function has recovered, avoiding multiple serum creatinine measurements or continuous urine output monitoring, which could lead to selection bias. Of course, our study has some highlights. Firstly, our research data are based on a large-scale critical care database with a certain time span and considerable sample size. Furthermore, we specifically focus on the diagnostic value of HDL-C in persistent severe SA-AKI which is an aspect with important clinical significance but less studied by researchers. This expands the knowledge boundaries of HDL-C and provides important references for basic research as well as clinical practice.

In summary, we have found that the HDL-C concentration within 24 h of ICU admission is not a good indicator for distinguishing between persistent and non-persistent severe SA-AKI, and it does not improve clinical prediction.