Lipid profile and statin use in critical care setting: implications for kidney outcome

ABSTRACT Objective: To determine whether pre-hospital statin use is associated with lower renal replacement therapy requirement and/or death during intensive care unit stay. Methods: Prospective cohort analysis. We analyzed 670 patients consecutively admitted to the intensive care unit of an academic tertiary-care hospital. Patients with ages ranging from 18 to 80 years admitted to the intensive care unit within the last 48 hours were included in the study. Results: Mean age was 66±16.1 years old, mean body mass index 26.6±4/9kg/m2 and mean abdominal circumference was of 97±22cm. The statin group comprised 18.2% of patients and had lower renal replacement therapy requirement and/or mortality (OR: 0.41; 95%CI: 0.18-0.93; p=0.03). The statin group also had lower risk of developing sepsis during intensive care unit stay (OR: 0.42; 95%CI: 0.22-0.77; p=0.006) and had a reduction in hospital length-of-stay (14.7±17.5 days versus 22.3±48 days; p=0.006). Statin therapy was associated with a protective role in critical care setting independently of confounding variables, such as gender, age, C-reactive protein, need of mechanical ventilation, use of pressor agents and presence of diabetes and/or coronary disease. Conclusion: Statin therapy prior to hospital admission was associated with lower mortality, lower renal replacement therapy requirement and sepsis rates.


❚ OBJECTIVE
To describe the modifications of lipid profile of critically-ill patients and their relation to outcomes in intensive care unit; to analyze the impact of pre-hospital admission statin therapy on renal outcomes and mortality: acute kidney injury, renal replacement therapy requirement and mortality rates.

❚ METHODS Type of study and subjects
This was a prospective cohort study that considered 670 patients sequentially admitted to the intensive care unit (ICU) of a teaching tertiary care organization. Previous 3HMG-CoA reductase inhibitors therapy was defined by patient record observation upon admission at ICU, since we considered the use of any specific statin during at least previous 6 months.
Patients aged over 18 years and who had ICU admission within the last 48 hours were included in the study. We excluded patients not to be considered for resuscitation, who underwent kidney transplantation, on chronic dialysis program, and who had already received RRT.

Laboratory analysis
A volume of 30mL of blood in ethylene diamine tetraacetic acid (EDTA) anti-coagulant was collected from each individual for renal function analysis (blood urea nitrogen and creatinine; Labtest ® , Lagoa Santa, MG, Brazil and the Jaffe modified method, respectively), lipid profile (HDL and LDL cholesterol; automated method equipment, Cell-Dyn Ruby; Abbott Diagnostics, Lake Forest, IL, USA), markers of systemic inflammatory response syndrome, CRP, albumin (Immunlite 1,000 immunoassay system, Erlangen, Germany), and the colorimetric method in automated equipment.
Charts were reviewed for clinical and epidemiological data and patients were allocated into Group Statin if they had prior statin use at least for the previous 6 months. Patients without prior statin use were allocated into Non-Statin Group.

Acute kidney injury and sepsis definition
Acute kidney injury (AKI) was defined according to Acute Kidney Injury Network (AKIN) criteria. (16) It was considered as AKI any decrease of renal function in the last 48 hours, characterized by an increase in absolute serum creatinine (sCr) of at least 26.5μmol/L (0.3mg/dL), an increase in sCr ≥50% (1.5-fold baseline value, or a decrease in the urine output (UO) <0.5mL/ kg/hour for more than 6 hours.
Acute renal injury stage 1 corresponds to the risk class, but it also considers an absolute increase in SCr einstein (São Paulo). 2019;17(3):1-8 ≥26.5μmol/L (0.3mg/dL). Stages 2 and 3 correspond to injury and failure classes, respectively. Stage 3 also includes all patients requiring RRT. Sepsis was defined based on the Surviving Sepsis Campaign Guidelines Committee. (19)

Primary endpoints
Our primary endpoints were occurrence of AKI, requirement of RRT and mortality.

Secondary endpoints
Our secondary endpoints were the occurrence of sepsis and determination of lipid profile of enrolled patients.

Statistical analysis
Data were analyzed using the software Statistical Package for the Social Sciences (SPSS) version 20.0 (SPSS, Inc., Chicago, IL, USA). Numerical data were presented as mean and standard deviation (SD) or as median and range. Categorical variables were expressed as total number and percentage.
Comparisons between groups were performed using Student t test for parametric variables. Non-parametric variables were compared using one-way analysis of variance (ANOVA) test, followed by Bonferroni as a posttest.
Binary logistic regression analysis was used to study variables associated with sepsis and RRT and/ or death. All results were considered significant at p<0.05. Groups were adjusted to age, sex, CRP levels, need of mechanical ventilation, use of vasopressors and presence of diabetes and coronary arterial disease.
Receiver Operating Characteristic (ROC) curve was used to demonstrate the accuracy of HDL-cholesterol dosage test in determining the risk of RRT need and/or mortality.
This study was carried out in compliance with ethical standards determined by resolution 466/12 of Conselho Nacional de Saúde, and approved by the Research Ethics Committee, opinion no. 1.290.566, CAAE: 23420414.9.0000.5505.

Demographic variables
Of the sample, 64% of patients were male. The mean age of patients included in this study was 66±16.1 years. They had a mean body mass index (BMI) of 26.6±4.9kg/m 2 and a mean abdominal circumference of 97±22cm (Table 1). Regarding the use of statins, 67 (54.5%) of the patients used atorvastatin, 43 (35.5%) simvastatin, 11 (9.1%) rosuvastatin and 1 (0.9%) used pravastatin. Pre-admission statin therapy demonstrated a protective role in our cohort of critically ill patients, resulting in an improvement of both kidney and patient outcome combined. Patients using statin prior to hospital admission were less likely to require RRT and/or die (OR: 0.4; 95%CI: 0.1-0.86; p=0.01) (     Table 3). The group that required RRT (n=91) and/or died had a lower percentage of patients using statin before hospital admission than Control Group (9.0% versus 19.6%; p<0.008), and had higher levels of CRP than the Control Group (14.8±22.8mg/dL versus 7.6±10.3mg/dL; p<0.001) at ICU admission (data not shown). Patients who required RRT or died had statistically significant lower HDL-cholesterol levels (p<0.05) ( The relation between low HDL-cholesterol levels and the combined outcome (RRT need and/or death) was demonstrated on ROC curve with the area under the curve of 0.727 for HDL (p<0.05). This relation was not present between LDL-cholesterol levels and the studied outcome ( Figure 1). The area under the curve demonstrates that lower high-density lipoprotein cholesterol and low-density lipoprotein cholesterol levels were associated with higher incidence of RRT need and/or death.

❚ DISCUSSION
The efficacy of statins in modifying cardiovascular risks is well established, even in patients with a normal lipid profile, which demonstrates the importance of the pleiotropic effects of this class of drugs. In our study, the pre-hospital statin use was associated with the attenuation on kidney dysfunction and sepsis outcomes in critical care setting. There are many similarities in the pathogenesis of atherosclerosis, sepsis and AKI, including inflammation and endothelial dysfunction. Regulation of any of these pathways may explain the beneficial effects of statins use in critical care. (6) It is known that critically ill patients develop metabolic changes, such as insulin resistance, disruption of cortisol metabolism and lipid profile, due to systemic inflammation. These metabolic modifications are similar to those seen in traditional metabolic syndrome and are noticed in both acute and recovery phase of systemic inflammation. (17) Lower HDL-cholesterol levels are markers of poor prognosis in critical care patients. In our study, a relation between HDL-cholesterol levels and patient outcome during ICU stay was clearly demonstrated, which is in agreement with the metabolic syndrome of critically ill patient hypothesis. These markers are associated with greater need of RRT incidence and higher mortality. We also found that those patients who developed AKI and required RRT had lower levels of HDL-cholesterol at ICU admission, and the magnitude of the observed reduction was also related with worse prognosis. Early reports have already characterized the metabolic syndrome of critical patients as hypertriglyceridemia and lower levels of HDL-cholesterol. Furthermore, it has also been suggested, in those previous studies, that the magnitude of change in lipid profile during systemic inflammation is proportional to the severity of inflammatory response and is related to patient's prognosis. (17,18) Murch et al., reviewed the pathophysiology of metabolic syndrome of critical patient, and demonstrated  that lipoproteins neutralize lipopolysaccharides and exert direct anti-inflammatory actions, suggesting that HDL and LDL particles are important regulators of human immune response to endotoxemia. (19) In addition, Wendel et al., had already shown that serum triglyceride levels frequently increase in systemic inflammatory conditions, such as sepsis, due to reduced triglyceride hydrolysis and fat oxidation, determining inflammation-insulin resistance and amplifying inflammation cascade. (20) Additionally, we demonstrated that a pre-admission use of statins was associated with lower rate of RRT requirement and/or mortality. During ICU stay, AKI is a well-known risk factor for death, particularly when RRT is required. Acute kidney injury in critical patients is usually due to many factors, such as dehydration, nephrotoxicity, inflammation and micro-thrombosis. Many mechanisms could explain the beneficial effect of statins in this scenario. Our group had already demonstrated the reversion of inflammatory imbalance at cell level, achieved with statin therapy. In that study, the treatment of peripheral mononuclear cells exposed to lipopolysaccharides of critically ill patients with simvastatin led to a decrease in interleukin 10 and tumor necrosis factor alpha (TNF-α) production, highlighting the immunomodulatory potential of such agents.
Statins are known to modulate endothelial function by promoting the synthesis of nitric oxide synthase enzyme, culminating in vasodilator effect and less oxidative injury. Studies with animal models suggest that statins have an inhibitory effect on leucocyte adhesion and transendothelial neutrophil migration, modulating the inflammatory response. (11) In acute scenarios, observational studies have already shown that HMG-CoA reductase inhibitors therapy is associated with lower incidence of CI-AKI after coronary angiography and percutaneous coronary intervention. The PRATO-ACS study has also demonstrated a relation of statin therapy on admission with better renal outcomes and lower CI-AKI incidence. (14) Statins are able to reduce protein endocytosis in the proximal tubule, resulting in less inflammation and tubular damage. Multiple mechanisms are involved in CI-AKI, but it is known that inflammation plays an important role. That is why the effect of statin therapy on reducing inflammatory cascade can be responsible for nephroprotective action of this class of drug. Likewise, pre-admission use of statin in critically ill patients may lead to better renal outcomes during ICU stay.
In agreement to our data, Singh et al., in their meta-analysis study, have shown a 33% reduction in the risk of RRT in the group of patients who received preoperative statin therapy before undergoing coronary artery bypass graft. (13) It has already been demonstrated that preoperative statin therapy was associated with a reduction in postoperative myocardial infarction, stroke and atrial fibrillation. On the other hand, Prowle et al., in a double-blinded, randomized controlled trial, failed to detect a protective effect of perioperative statin therapy on AKI after cardiac surgery with cardiopulmonary bypass. (21) In our study, as a secondary endpoint, we found that pre-hospital use of statins was associated with lower rate of sepsis during ICU stay, since this class of drug can modulate the inflammatory response in its initial phases, when organ dysfunction is not yet established. Our group had already shown that peripheral blood mononuclear cells isolated from critically ill patients with AKI when treated with simvastatin had lower TNF-α production than that of healthy Control Group. Currently available evidence suggests, as seen in our study, that the pleiotropic effects of statin could be beneficial during sepsis. In fact, Feng et al., demonstrated that in patients with sepsis using rosuvastatin as the reference, atorvastatin and simvastatin had superior efficacy in preventing mortality. (22)(23)(24)(25)(26)(27)(28)(29)(30) Additionally, Craig et al., reported in their randomized, double-blinded, placebo-controlled trial, that some components of Sequential Organ Failure Assessment (SOFA) score, such as coagulation, renal and cardiovascular components, were improved at day 14 in simvastatin group. This improvement in organ dysfunction is considered to be related to the effect of statin on preservation of endothelial function. (31)

Limitations
The present study demonstrated evidence of a beneficial role of using statins in critical care patients. Our results were generated, primarily, based on a prospective analysis, but some confounders could not have been measured. It also has a small sample of patients, which may contribute to statistical limitations. The heterogeneity of type and dosage of statin used by patients in our study may also lead to difficulties in analysis. It was also a single-center study, restricted primordially to patients with clinical pathologies.
Large-scale prospective clinical trials are needed to deepen our knowledge in this field. Moreover, it is still not clearly known the extent and kind of side effects of statins in critically ill patients.

❚ CONCLUSION
Critically ill patients present peculiar lipid profile modifications that are closely related to the magnitude of inflammatory response, leading to what is called metabolic syndrome of intensive care unit. Statin therapy prior to hospital admission was associated with better outcomes during intensive care unit stay, such as lower risk for renal replacement therapy requirement and/or mortality, probably attributed to its pleiotropic effects on inflammation, endothelial regulation, and oxidative stress damage.

❚ ACKNOWLEDGMENTS
To the Coordenação de Apoio de Pessoal de Nível Superior (CAPES). None of the authors present a personal or financial conflict of interest.

❚ AUTHORS' CONTRIBUTIONS
IM and MCB designed research; IM and BMQ conducted research; BMQ, MSDJR, JCMM and OFPS, provided essential materials; IM, MCB and BMQ, analyzed data or performed statistical analysis; IM, wrote paper; IM and MCB, had primary responsibility for final content. All authors read and approved the final manuscript.