This study examined the relationship between obesity, AKI, and ARDS mortality. In our cohort, obesity was an independent risk factor for AKI not explained by greater severity of illness or shock. Increasing BMI was significantly associated with increased development of AKI but decreased all-cause 60-day ARDS mortality. ARDS patients with AKI had a higher mortality even after adjusting for BMI and other mortality predictors. Consistent with the rapid onset of end-organ failures in critically ill patients, most of the cohort had AKI on the day of ICU admission. There were no differences on the time to development of AKI by BMI categories. Obesity was associated with more ICU-free days and VFDs but longer hospital LOS compared to normal BMI.
This study has several strengths. First, it had a large sample size and included medical and surgical patients with common ICU conditions that are known causes of ARDS. Second, since the worst Cr was available daily in all patients for the entire study period, development of AKI could be assessed for all patients. Lastly, we examined 60-day mortality instead of ICU or hospital mortality since this outcome parameter is more clinically relevant to the critically ill population with AKI (31
A prior study using data from the first NHLBI ARDS Network trials found a much lower prevalence of AKI in ALI patients (24%) than in our cohort (61.9%) (18
). This could be explained by different diagnostic criteria used for AKI. In our study the baseline Cr was estimated from the MDRD equation while Liu’s study used the lowest Cr on day 0 as baseline which may represent already existing renal dysfunction on ICU admission and would underestimate the true change in Cr and the extent of AKI. Using similar AKI criteria as Liu’s in our cohort, we still found a higher prevalence of AKI (53.7%) with the same association between BMI and AKI and a protective effect of BMI on mortality.
The use of GFR to determine RIFLE criteria for AKI might overestimate AKI in patients with higher BMI because of higher muscle or bone mass. We did not correct for body surface area (BSA) in the GFR equation which may overestimate the renal excretory function among the obese (32
). However, the BSA equations have not been validated in obese patients because of their lack of accuracy and performance in these patients and the lack of proof that using actual BSA improves the accuracy of the MDRD equation (33
). Therefore, it is not standard practice to correct the GFR for the patient’s BSA and we did not perform such correction in this study. Furthermore, in our cohort, AKI was associated with higher mortality rates in every BMI category and obese and severely obese patients with Failure had higher mortality than those with less severe renal dysfunction. Therefore, it is unlikely that the higher prevalence of AKI in our obese and severely obese patients may be attributed to an overestimation of renal function from a BSA-uncorrected GFR and our results suggest that AKI may represent true organ dysfunction.
There is limited data on the possible pathophysiological mechanisms for the observed relationship between obesity and AKI. Animal studies have shown a possible link between leptin and renal injury. In humans with obesity, leptin levels may be inappropriately high due to hyporesponsiveness to leptin (35
) but the levels decline rapidly during fasting (36
). In patients with CKD, leptin is elevated due to decreased plasma clearance and increased production (37
). A clinical study found normal plasma leptin levels prior to first dialysis in patients with AKI and no significant differences in leptin levels between survivors and non-survivors with AKI (38
). In this study, AKI and CKD patients had similar mean BMI (26 kg/m2
vs. 26.3 kg/m2
). In a leptin-deficient animal model of obesity (ob/ob mice), leptin-deficient obese mice were much more susceptible to endotoxin-related AKI than their lean littermates (39
). Ob/ob mice had a significant decrease in GFR and exhibited histological evidence of acute tubular necrosis after endotoxin (LPS) administration. These pathological changes were mild as observed in human AKI. When ob/ob mice developed shock with a higher dose of LPS, leptin replacement offered protection against AKI with significant improvement in mean arterial pressure and decrease in serum Cr. These beneficial effects suggest a leptin-mediated effect on peripheral vascular resistance.
Interleukin (IL)-18, a pro-inflammatory cytokine, is systemically elevated in obesity (40
) and directly correlates with BMI (41
). Urinary IL-18 is associated with increased development of AKI in critically ill patients (43
), but it is not clear whether IL-18 is a causal factor or merely an early marker of AKI. In the ARDS Network trials, urinary IL-18 was elevated earlier than plasma Cr and the urinary IL-18 values were also significantly different between survivors and non-survivors. Furthermore, urine IL-18 on day of ARDS diagnosis was an independent predictor of ARDS mortality (44
). It is unclear whether increasing BMI is related to AKI by an IL-18 mediated mechanism. However, the limited data available suggest that there may be a biological factor related to leptin- or IL-18 mediated effects that may be associated with AKI.
Our results show that critically ill patients with AKI have worse prognosis as documented in other studies (6
). Yet, we found a much higher mortality by RIFLE category than the study by Hoste (Risk = 8.8%, Injury = 11.4%, Failure = 26.3%) (6
) probably because our study examined patients at higher risk of death (ARDS) and Hoste’s study included an unselected group of critically ill patients. Even if AKI was associated with higher mortality in each weight group, BMI was associated with lower mortality. This is supported by prior studies in ALI/ARDS that showed either a trend for a protective mortality effect by obesity (3
) or a significantly lower mortality in obese patients (47
). However, our study differed from others that reported either a higher ICU mortality (48
) or no association with 28-day mortality with obesity (49
). This may be explained by differences in sample size, study design, or patient characteristics. The study by Gong included 547 ARDS patients with a trend towards less mortality in univariate analysis and a non-significant protective effect on multivariate analysis (3
). With the larger sample size in our study, this protective effect of BMI on mortality became statistically significant. Bercault included 170 pairs of patients from a single ICU who were matched on 8 clinical criteria which could have biased the results due to overmatching. O’Brien excluded underweight patients, who have higher mortality, and the most likely cause of ALI in overweight and obese patients was trauma which is the risk factor for ALI with the best outcomes (50
). In our cohort, the underweight had a higher mortality and died sooner than obese patients most likely because they were older, had a higher severity of illness, had more shock and ARDS on the day of ICU admission, more chronic liver disease, and were exposed to the highest TV per IBW on the day of ARDS diagnosis. Further research to elucidate the mechanisms behind the paradoxical survival benefit in the obese critically ill is needed. One possible explanation is that since acute illness is associated with a high catabolic state, the increasing adipose tissue in obese patients could be used as nutritional and energy support during highly catabolic conditions.
There are several limitations to this study. First, because the parent study focused on risk factors for development and mortality of ARDS, we lack data on blood urea nitrogen, volume status, fluid resuscitation, daily urine output, or new dialysis. However, the highest daily Cr during the 28 days of the study period was available. Second, although we had data on diabetes, we did not have information on other relevant comorbidities (e.g., hypertension and peripheral vascular disease), or other risks factors for AKI (e.g., contrast dye, aminoglycosides, or other nephrotoxic drugs). Third, BMI was examined in this study rather than other potentially more reliable measures of body composition such as the waist-to-hip ratio (51
). Fourth, although weight was determined on ICU admission, we cannot exclude the possibility that fluids given prior to admission may have affected BMI as well as the volume of distribution of Cr which may affect its measurement. Additionally, we determined baseline Cr from the MDRD equation which could overestimate the prevalence of AKI in CKD. However, we did exclude ESRD patients and a sensitivity analysis of 202 random patients indicated minimal (1%) misclassification of AKI using MDRD-estimated Cr. Also, this study did not include an assessment of processes of care (e.g., criteria for RRT initiation) that could account for some of the observed differences in the results among BMI groups. Lastly, this study was limited to patients with ARDS who were predominantly Caucasian and the results may not be generalizable to other populations of critically ill patients or other racial groups.