Introduction:
Acute Kidney Injury (AKI) is characterised by sudden decrease in renal function, increase in serum creatinine and/or decrease in urine output.(1) AKI is a frequent complication among critically ill patients and especially among patients with sepsis. It has been associated with increased morbidity and mortality as well. Sepsis is a clinical condition which is characterized by inflammation and dysregulated immune response to infection.(2) Sepsis is the most common cause of AKI among ICU patients and sepsis related AKI (S-AKI) has been associated with greater severity of disease and severe sepsis.(2) It leads to longer duration of hospital stay, increased burden on the health care and delay in recovery from illness compared to non-septic causes of AKI. Reported incidence of AKI in Intensive Care Unit (ICU) varies between 16% to 67%, of which sepsis as a cause for AKI ranges between 26%-50% sometimes as high as 75%.(3-5) Increasing severity of sepsis increases the odds of developing AKI and S-AKI itself is an independent predictor of fatal outcome.(2)
Pathophysiology of sepsis induced AKI is varied and multi factorial and newer insights are implicated in S-AKI. Earlier proposed mechanism is decreased renal perfusion leading to ischemic insult resulting in tubular necrosis. But occurrence of S-AKI with preserved renal blood flow and absence of hemodynamic instability refutes this claim and paradigm shift has happened in pathophysiology underlying S-AKI.(6,7) Newer insights proposed for S-AKI includes microvascular dysfunction, inflammation and oxidative stress, Tubular epithelial cell (TEC) survival strategy and metabolic reprogramming.(8-10) In S-AKI, heterogeneity in microcirculation with distorted distribution in peritubular and glomerular blood flow occurs.(2,9) TEC adapts a strategy wherein downregulation of non-vital cellular function to evade cell death despite trigger for apoptosis occurs and TEC decides the repair phenotype once inflammation subsides.
Mortality due to non-septic AKI is 16% whereas mortality reported in S-AKI is 38% in a study by Pinheiro et al.(11) Estimates of mortality due to S-AKI ranges between 10 to 50 percent in different studies in different setups in different countries and estimated 6-8 fold increase in mortality is observed with S-AKI.(12) Mortality is lesser amongst younger patients of age <45 years with lesser comorbidities.(13) Recovery of renal function does not occur in a subset of patients having persistent inflammation causing interstitial fibrosis which leads on to End Stage Renal disease (ESRD) on follow up and in a proportion of patients lag time to recovery may take several months.(14) Despite recovery and survival of sepsis such patients tend to have a decrement in the quality of life on follow up.(15) Data on clinical profile and outcome of patients with septic AKI remains to be explored. Though studies have been reported globally in AKI among ICU patients, studies of AKI in severe sepsis are limited particularly in developing Asian countries like India. Our study aims to study clinical profile and outcome of Severe sepsis related AKI and factors associated with fatal outcomes among patients with severe sepsis and AKI.
Methodology:
This was an observational prospective study done over a period of 18 months (February 2014 to August 2015) in a multi-disciplinary Intensive Care Unit (ICU) of a tertiary care centre in Chennai, South India. All patients admitted to ICU with severe sepsis were studied and evaluated for acute kidney injury as per the study inclusion and exclusion criteria.
OBJECTIVES: The primary objective is to study the clinical profile and outcome of Acute Kidney Injury (AKI) in Severe Sepsis and assess the factors associated with mortality among patients with AKI and severe sepsis.
Patients aged ≥ 18 years who satisfied the case definition for severe sepsis or septic shock and acute kidney injury were included. Patients on renal replacement therapy prior to current hospitalization and patients referred from other hospitals intensive care unit for continuing inpatient care were excluded from the study. Total 304 patients satisfied inclusion and exclusion criteria. Informed consent from either the patient (alert participants) or closest family member (in less alert or confused participants) was obtained for all the participants enrolled in the study.
Case definitions: Sepsis was defined according to International guidelines for management of sepsis 2012.(16)
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Systemic Inflammatory Response Syndrome (SIRS) is defined as presence of any two or more of the following, (i)Fever (oral temperature >38°C) or hypothermia (oral temperature <36°C), (ii)Tachypnoea (>24 breaths/min), (iii)Tachycardia (>90 beats/min), (iv)Leucocytosis (>12,000/µL), leukopenia (<4000/µL), or >10% bands.
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Sepsis is defined as SIRS with a proven or suspected microbial aetiology.
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Severe sepsis is defined as sepsis-induced organ dysfunction or tissue hypo perfusion. Severe sepsis is indicated by one or more of the following: (i) Sepsis induced hypotension- defined as a systolic blood pressure (SBP) < 90 mm Hg or mean arterial pressure (MAP) < 70 mmHg or a SBP decrease > 40 mm Hg or less than two standard deviations below normal for age in the absence of other causes of hypotension, (ii) Serum lactate above upper limits of laboratory normal value (>2mmol/L), (iii) Acute lung injury (ALI) with PaO2/FiO2<250 in the absence of pneumonia as infection source or acute lung injury with PaO2/FiO2<200 in the presence of pneumonia as infection source, (iv) Creatinine >2.0 mg/dL, (v) Bilirubin >2 mg/dL, (vi) Platelets count < 1,00,000/µL, (vii) Coagulopathy (INR) > 1.5.
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Acute kidney injury (AKI) is defined as elevation in serum creatinine by 1.5 times (50%) from baseline value or increase in serum creatinine by 1.5 times (50%) during the first 48 hours of hospitalization. AKI occurring in the first 48 hours of admission is defined as early AKI, whereas late AKI is the one developing after 48 hours of admission to hospital.
Details of presenting history, past and personal history was obtained followed by clinical examination and findings were recorded in a structured data collection sheet along with details of initial investigations and treatment. Patients were followed up throughout the course of hospital stay and details of investigation, treatment and clinical course including complications were recorded. Source of sepsis, need for mechanical ventilation, vasopressor need, RRT requirement were noted.
Outcome was categorized as Survivors and Non-Survivors. Amongst the survivors, they were further classified as patients with renal recovery and those without renal recovery based on renal status at the time of discharge. Variables such as age, gender, co-morbidities, primary focus of sepsis, need for ventilator, day of onset of AKI were compared between survivors and non-survivors for outcome prediction.
Ethics approval: The study was duly approved by Institutional Ethics Committee (CSP-MED/14/FEB/12/41).
Statistical Analysis:
Continuous variables were expressed as mean and categorical variables were expressed as number (%). Descriptive variables included gender, age, prior medical comorbidities, admission laboratory parameters, foci of sepsis, proportion of patients with early versus late AKI, severity of renal injury, need for ventilator and outcome. The collected data was analysed with SPSS for windows, version 16.0, Chicago Inc. To describe about the data descriptive statistics frequency analysis, percentage analysis was used for categorical variables and the mean for continuous variables. To find the significant difference between the bivariate samples in the independent groups (Death & Recovered) unpaired sample t-test was used. To find the significance in categorical data Chi-Square test was used. A p value of < 0.05 was considered statistically significant.
Results:
Three hundred and four patients were studied in total, amongst them males were predominant (n=207, 68.1%) and females were 31.9% (n=97). Majority were in the age group 40 to 80 years (79%). Most commonly observed comorbidities include diabetes (56%) followed by hypertension (44%). Baseline characteristics and outcome of study patients is presented in Table-1.
Table 1: Baseline Characteristics and Outcome of Study Participants |
Variable |
Number (n) |
Percentage (%) |
Gender |
Male |
207 |
68.1% |
Female |
97 |
31.9% |
Age (in years) |
19-40 |
45 |
14.8% |
41-60 |
117 |
38.5% |
61-80 |
123 |
40.5% |
>80 |
19 |
6.3% |
Comorbid conditions |
Diabetes |
169 |
55.6% |
Hypertension |
134 |
44.1% |
Coronary artery disease |
53 |
17.4% |
Previous stroke |
29 |
9.5% |
Dyslipidemia |
104 |
34.2% |
Survivors |
101 |
33.2% |
Non-survivors |
203 |
66.8% |
Renal recovery-yes |
79 |
26% |
No renal recovery |
225 |
74% |
Mean day of AKI onset was 1.62 days. Observed mean value of baseline laboratory variables includes white cell count (WBC) of 18877 cells/mm3, serum sodium (133 meq/L), serum potassium (4.4 meq/L), serum chloride (99 meq/L), serum bicarbonate (18meq/L), serum aspartate aminotransferase (AST, 97 IU/L), serum alanine aminotransferase (ALT, 112 IU/L), serum alkaline phosphatase (ALP, 136 IU/L). Mild serum albumin-globulin ratio reversal was noted with mean serum albumin of 3.1g/dl and mean serum globulin of 3.2g/dl. 74.6% (n=227) required ventilatory support and 21.7% (n=66) required renal replacement therapy (RRT). One hundred and one patients survived (33.2%) and non-survivors were 203 patients with observed mortality rate of 66.8%. Though males were predominant in our study, gender wise distribution showed that women and men had similar mortality rates at 68% and 66.2% respectively (p=0.749). Respiratory foci (n=97, 31.9%) was the most common source of severe sepsis noted in our study followed by urinary tract source (n=62, 20.39%). Overall among non-survivors, most common source of sepsis was respiratory tract (36.9%) followed by septicaemia with unknown foci (18%). Survivors commonly had urinary tract source, soft tissue infection, central nervous system (CNS) infection as cause for sepsis. 80.9% (n=246) had early AKI (<48hours) and 19% (n=58) had late AKI (>48 hours).
Table 2: Primary foci of Infection among Survivors and Non-survivors and its association with Outcome |
Foci of infection |
Non-survivors, n (%) |
Survivors, n (%) |
p value |
Respiratory foci (a) (n=97) |
75 (77.3%) |
22 (22.7%) |
0.008 |
Urinary tract source (n=62) |
31 (50%) |
31 (50%) |
0.002 |
Intrabdominal source (b) (n=25) |
20 (80%) |
5 (20%) |
0.143 |
Soft tissue infection (n=55) |
28 (50.9%) |
27 (49.1%) |
0.006 |
Septicaemia with no foci (n=46) |
37 (80.4%) |
9 (19.5%) |
0.065 |
CNS infection (c) (n=19) |
12 (63.2%) |
7 (36.8%) |
0.729 |
a: Respiratory source includes pneumonia, lung abscess, empyema; b: Intraabdominal source includes splenic abscess, liver abscess, colitis, cholangitis, spontaneous bacterial peritonitis (SBP), perianal abscess; c: CNS infection includes pyogenic meningitis, encephalitis, tuberculous meningitis, epidural abscess. |
Association between primary source of infection and outcome among patients with severe sepsis is shown in Table 2. In our study, sources of severe sepsis which were significantly associated with fatal outcome includes respiratory tract (p=0.008), urinary tract source (p=0.002) and intraabdominal source (p=0.006). Survivors had higher renal recovery (65.34%) compared to non survivors (6.4%). Among those who had renal recovery, 6.4% (n=13) still succumbed to illness whereas 34.6% (n=35) of non-survivors had renal recovery. Variables associated with mortality among patients with severe sepsis related AKI were source of sepsis which includes respiratory foci (p=0.008), urinary tract source (p=0.002), intraabdominal sepsis (p=0.006), need for mechanical ventilatory support (p < 0.001).
Table 3: Comparison of Variables between Survivors and Non-survivors |
Variables |
Non-survivors, n(%) (n=203) |
Survivors, n(%) (n=101) |
p value |
Gender |
Male (n=207) |
137 |
70 |
0.749 |
Female (n=97) |
66 |
31 |
Age in years |
19-40 (n=45) |
37 (18.2%) |
8 (7.9%) |
0.05 |
41-60 (n=117) |
72 (35.5%) |
45 (44.6%) |
61-80 (n=123) |
79 (38.9%) |
44 (43.6%) |
>80 (n=19) |
15 (7.4%) |
4 (4%) |
Diabetes (n=169) |
106 |
63 |
0.093 |
Hypertension (n=134) |
89 |
45 |
0.906 |
CAD (n=53) |
33 |
20 |
0.443 |
CVA (n=29)
|
20 |
9 |
0.792 |
Dyslipidemia (n=104) |
65 |
39 |
0.254 |
Ventilatory support (n=227) |
202 |
25 |
<0.001 |
Increasing age though had more fatal outcomes, it was insignificant (p=0.05). Gender (p=0.749), underlying comorbidities were not significantly associated with mortality in our study as shown in Table-3. Since ventilator requirement had a strong association with mortality in our study, we compared source of sepsis with need for mechanical ventilation support and we observed respiratory tract source (p=0.015), urinary tract foci (p=0.002) and soft tissue infection (p=0.006) had a significant association with mechanical ventilation requirement.
Table 4: Comparison between Source of Sepsis and Ventilator need in Study Patients |
Foci of sepsis |
Required Ventilator support, n (%) |
No ventilator support, n (%) |
p value |
Respiratory foci (n=97) |
81 (83.5%) |
16 (16.5%) |
0.015 |
Urinary tract source (n=62) |
37 (59.7%) |
25 (40.3%) |
0.002 |
Soft tissue infection (n=55) |
33 (60%) |
22 (40%) |
0.006 |
Intrabdominal source (n=25) |
22 (88%) |
3 (12%) |
0.110 |
Sepsis with no foci (n=43) |
36 (83.7%) |
7 (16.3%) |
0.14 |
Table-4 shows comparison between source of sepsis and ventilatory requirement among study patients. Three primary foci of sepsis which had strong association with mortality and ventilator need observed in our study includes respiratory sepsis, urosepsis and soft tissue sepsis which on further analysis in the trend of early AKI vs Late AKI did not had any significant association with occurrence of timing of onset of AKI (p=0.089, p=0.114, p=0.259 respectively).
Table 5: Comparison of Sepsis Foci with Onset of AKI |
Source of infection |
Early AKI (<48hours), n (%) |
Late AKI (>48 hours), n (%) |
p value |
Respiratory foci (n=97)
|
72 (74.2%) |
25 (25.8%) |
0.089 |
Urinary tract source (n=62) |
54 (87.1%) |
8 (12.9%) |
0.114 |
Soft tissue infection (n=55) |
47 (88.5%) |
8 (14.5%) |
0.259 |
Source of sepsis with occurrence of onset of AKI is presented in Table 5. Among the laboratory variables, increase in white cell count (leucocytosis) and metabolic acidosis (mean serum bicarbonate < 20meq/L) was relatively higher in the subgroup who had early AKI (<48 hours). Table 6 shows observed laboratory parameters between early AKI and late AKI group.
Table 6: Mean Values of Laboratory Variables and Ventilator need Observed between Early AKI and Late AKI group |
Variables |
Early AKI (<48 hours) |
Late AKI ( > 48 hours) |
Survivors (n=97) |
Non-survivors (n=149) |
Survivors (n=4) |
Non-survivors (n=54) |
White blood cell count (cells/mm3) |
18043 |
22217 |
10700 |
11767 |
Serum sodium (meq/L) |
133 |
133 |
136 |
133 |
Serum bicarbonate (meq/L) |
18 |
16.5 |
23 |
21 |
Serum albumin (g/dl) |
3.2 |
3.0 |
3.6 |
3.1 |
Serum globulin (g/dl) |
3.1 |
3.2 |
2.5 |
3.4 |
Ventilator support required |
24 |
148 |
1 |
54 |
Discussion
This is an observational study conducted in a tertiary care hospital to study profile and outcome of Severe sepsis related AKI. AKI can perpetuate infection and sepsis makes the host prone for AKI making the cause and effect relationship difficult to ascertain.
Baseline characteristics: In our study majority were above 60 years (46.71%) and males were predominant (68%). Elderly population are at high risk of developing S-AKI and adverse outcome. Increasing age is a predictor of mortality associated with S-AKI.(17) Gender impact on S-AKI remains unclear. Though males were predominant in our study, gender did not have any significant association with mortality. Bagshaw et al observed females were at high risk of developing S-AKI.(18) Underlying medical conditions did not increase mortality risk secondary to S-AKI in our study. In contrast Oppert M et al noted comorbidities puts at risk patients with sepsis vulnerable for developing AKI and portends adverse outcome.(19) Length of stay in ICU for S-AKI patients is twice that of non-septic AKI patients which increases morbidity and health care expenses burden on family members.(17)
Early vs Late AKI: Bagshaw SM et al observed sepsis related AKI to have more acute presentation with more severe acidosis and deranged biochemical parameters, higher markers of inflammation, higher Sequential Organ Failure Assessment (SOFA) scores, increased need for vasopressors compared to non-sepsis related AKI.(17,20) Similarly in our study, S-AKI had mean onset < 2 days in 80% of patients and non survivors in early AKI had higher mean white cell count (22217 cells/mm3) and severe acidosis (mean serum bicarbonate 16.5meq/L). Freitas et al noted no difference in mortality amongst early or late AKI.(21)
Source of sepsis and outcome: Commonly observed sources of sepsis in our study in sequence were respiratory followed by urinary tract and soft tissue infection. All three foci of sepsis had a significant association with mortality though it did not had association with timing of onset of AKI. Similar to our study, Park DW et al noted AKI commonly among patients with respiratory foci followed by urinary tract source and soft tissue infection.(22) In a meta analysis by Liu J et al, respiratory source followed by intra abdominal foci were common source of S-AKI and strikingly they observed lesser likelihood of death with respiratory sepsis and higher odds of death with intraabdominal sepsis. Contrasting results by Liu J et al is likely due to heterogeneity as Chinese cohort in subgroup analysis had respiratory sepsis associated with increased mortality.(23) We observed a mortality rate of 66.8%, varying mortality rates have been seen in different studies ranging from 28% to 76%. Eswarappa et al observed a mortality rate of 37.6% among Indian cohort.(24) Degoriaja et al reported varying mortality rates for different severity of sepsis as 17% in sepsis, 22.7% in severe sepsis, 72.1% in Septic shock and 74.4% in patients with MODS.(25)
Invasive mechanical ventilation poses higher odds of developing AKI and neither tidal volume (TV) nor positive end expiratory pressure (PEEP) modifies this risk.(26) In our study ventilator requirement had significant association with fatal outcome. Hoste EA et al found need for mechanical ventilation and renal replacement therapy as an independent predictor of mortality.(17) We observed renal recovery rate of 26% overall compared to Eswarappa et al reported rate of 60% in his study.(24)
Limitations of our study: All patients with sepsis were not taken into the study and only patient who had AKI or developed AKI in hospital are taken into study, hence the study does not inform about risk factors for developing AKI in severe sepsis. Our diagnostic criteria of AKI which excluded the poorly correlating hourly urine output parameter and relying on absolute increment of creatinine from patient’s prior baseline or current baseline needs further validation using additional newer GFR markers.
Conclusion:
Our study observed a mortality rate of 66.8% among severe sepsis patients with acute kidney injury. Patients with respiratory sepsis had a higher mortality of 77.3%. Survivors had higher renal recovery (65.34%) compared to non survivors (6.4%). Early AKI was commonly observed in severe sepsis than late AKI. Respiratory tract, urinary tract and soft tissue source of sepsis, need for ventilatory support were significantly associated with mortality in patients with severe sepsis and AKI.
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