1.Literature search (Figure 1)
8033 records from the Medline, Embase, Cochrane Library, PubMed and Web of Science databases were initially identified. After filtering by title and abstract, most of them are excluded due to the duplicate, review, or unrelated topic. After 626 studies were reviewed in full text, 579 articles were excluded according to review and comments papers, inconsistent control settings, unknown AKI or sepsis diagnostic criteria, special population, duplicate and limited data. Finally, 47 articles including 22 sepsis,12 septic shock,5 severe sepsis and 8 others met the inclusion criteria and were conducted systematic review and meta-analysis.
2.Characteristics of Included Studies (table 1)
The characteristics of the included articles are shown in table 1. Studies were published between 2008 and 2019, and were from eighteen countries (Spain, Greece, United Kingdom, France, Netherlands, Sweden, Canada, United States, Brazil, China, Japan, Saudi Arabia, Turkey, Finland, Portugal, South Korea and Australia) on four continents (Europe, America, Asia and Oceania). All studies were observational including 12 retrospective cohorts, 25 prospective cohorts and 12 case-control studies. A total of 55911 sepsis patients were included in the analysis. Document quality assessment shows that the methodological quality of all studies is high, achieving a quality score of ≥6 of 8.
3.Summary data from included studies (table 2)
This study summarized the characteristics of sepsis patients who developed AKI. ICU mortality, hospital mortality,28-day mortality and 90-day mortality of S-AKI were respectively reported at 45.99% (1989/4325) in 15 studies,49.84% (2732/5481) in 10 studies, 36.67% (161/439) in 4 studies, 64.66% (2406/3721) in 5 studies. The 90-day mortality is the highest. In S-AKI patients, all mortality rates of AKI caused by septic shock are the highest, while that caused by severe sepsis was the lowest.
Regarding comorbidities, the most common one is ARDS (47.02%, 489/1040, from 3 studies), followed by hypertension (38.39%,3263/8500,from 32 studies), diabetes (27.57%,2248/8155, from 32 studies) and stroke (22.79% ,67/294,from 4 studies). Cirrhosis and Liver disease were the least common and account for only (4.71% ,99/2104, from 6 studies) and (3.74%,554/14081, from 7 studies). Hepatic failure in sepsis were more common in sepsis than in septic shock and severe sepsis. Hypertension in septic shock is less common than sepsis and severe sepsis (26.16% VS 42.28% and 58.07%), while Chronic kidney disease was more prevalent (45.13% VS 15.52% and 11.02%). Hypertension and diabetes were more prevalent in severe sepsis than in sepsis and septic shock (58.7% VS 42.28% and 26.16%,30.20% VS 20.53% and 26.75%).
On admission, patient mainly comes from emergency admission (50.88%, 9235/18149, from 8 studies) and medical admission (47.02%,8701/18506, from 7 studies), followed by operative admission and surgical ward. In the use of Medications, vasoactive drugs are the most commonly used drugs, accounting for 64.61% (1293/2001, from 5studies), and vasopressors among vasoactive drugs is the most frequently used, accounting for 63.22% (911/1441, from 7 studies), followed by steroids, diuretics, ACEI or ARB, stains and NSAIDS. vasoactive drugs and vasopressors were more prevalent in septic shock and severe sepsis than in sepsis.
Six sources of infection were reported in this study, with the order of occurrence rate from high to low being the following: pulmonary(46.05%,1480/3214, from 19 studies), respiratory(32.08%,85/273, from 7 studies), abdominal(30.87%,2152/6971, from 25 studies), Urinary tract (11.14%, 630/5653, from 19 studies), skin or soft tissue (6.03%, 335/5554, from 13 studies), unknow (6.02%, 100/1662,from 4 studies).
Community acquired infection was reported in 3 studies at 57.36% (2041/3558), which was higher than nosocomial acquired infection reported in 2 studies at 39.81% (2474/6215). Twenty-four studies reported mechanical ventilation in 68.00% (7167/10539, from 24 studies), and mechanical ventilation in septic shock and severe sepsis was more prevalent than in sepsis. Other prevalent factors include positive blood culture (41.38%,3259/7876, from 8 studies), Smoke history (43.09%,642/1490, from 5 studies).
4.Risk Factor Analysis of AKI
Comorbidities
Hypertension was pooled from 32 studies with a significant (OR,1.43;95%CI:1.20-1.70), moderate heterogeneity(I2=74.00%). Sources of heterogeneity were not identified using subgroup analysis. The results of the sensitivity analysis are consistent. After 3 studies with heterogeneity is excluded, the heterogeneity decrease and the result remains stable.
Diabetes mellitus was pooled from 32 studies with a significant (OR 1.59;95%CI:1.47-1.71), moderate heterogeneity(I2=37.1%). The results are still stable after using the random effects model.
Chronic kidney disease was pooled from 14 studies with a significant (OR,3.49;95%CI:2.36-5.15), moderate heterogeneity(I2=71.70%). Sources of heterogeneity were not identified using subgroup analysis. The results of the sensitivity analysis are consistent. After a study with heterogeneity is excluded, the heterogeneity among studies was reduced to low heterogeneity (25.6%) and the result remains stable.
Cardiovascular disease (from 14 studies, OR,1.31;95%CI:1.24-1.40), liver disease (from 17 studies, OR, 1.68;95%CI: 1.47-1.90) were all low heterogeneity and identified as risk factors. Their results are still stable after using the random effects model.
Coronary artery disease was pooled from 8 studies with a significant (OR,1.27;95%CI:1.08-1.49), moderate heterogeneity(I2=37.1%). The results are still stable after using the random effects model.
Source of infection
Pulmonary infection was pooled from 8 studies with a significant (OR,0.77;95CI:0.60-0.99), moderate heterogeneity (I2= 77.60%). Sources of heterogeneity were not identified using subgroup analysis. The results of the sensitivity analysis are consistent.
Abdominal infection was pooled from 25 studies with a significant (OR,1.44; 95%CI:1.32-1.58), moderate heterogeneity (I2= 40.20%). The results of the sensitivity analysis are consistent. After a study with heterogeneity is excluded, the heterogeneity disappears and the result remains stable. The results are still stable after using the fixed effects model.
Unknow infection was pooled from 25 studies with a significant (OR,2.01;95CI:1.35-2.98), low heterogeneity(I2=0%). The results are still stable after using the random effects model.
Medications
Vasoactive drugs were pooled from 5 studies with a significant (OR,3.85;95%CI:1.89-7.87), high heterogeneity (I2=86.40%). After a study with heterogeneity is excluded, the heterogeneity disappears and the result remains stable. The results of the sensitivity analysis are consistent.
Vasopressors (from 7 studies, OR, 3.15;95%CI: 2.00-4.96) and ACEI or ARB (from 8 studies, OR,1.61;95%CI:1.10-2.36) were all high heterogeneity(I2≥75%) and identified as risk factors. Sources of heterogeneity were not identified using subgroup analysis and their results of the sensitivity analysis are stable
Diuretics was pooled from 5 studies with a significant (OR,1.40;95%CI:1.13-1.72), low heterogeneity(I2=0%). The results are still stable after using the random effects model.
Other factors
Male sex was pooled from 43 studies with a significant (OR,1.22;95%CI:1.06-1.40), moderate heterogeneity(I2=69.80%). Sources of heterogeneity were not identified using subgroup analysis. The results of the sensitivity analysis are consistent.
Gram-negative bacteria (from 3 studies, OR, 2.19;95%CI:1.52-3.15) and organ transplant (from 3 studies, OR,1.96;95%CI:1.48-2.61) were all low heterogeneity(I2=0%) and identified as risk factors. Their results are still stable after using the random effects model.
Mechanical ventilation was pooled from 24 studies with a significant (OR,1.64;95%CI:1.24-2.16), high heterogeneity (I2=88.70%). Sources of heterogeneity were not identified using subgroup analysis. he results of the sensitivity analysis are consistent.
Positive blood culture was pooled from 9 studies with a significant (OR,1.60;95%CI:1.35-1.89), moderate heterogeneity(I2=50.20%). Sources of heterogeneity were not identified using subgroup analysis. The results of the sensitivity analysis are consistent.
Smoke history was pooled from 5 studies with a significant (OR,1.60;95%CI:1.09-2.36), high heterogeneity(I2=78.30%). The results of the sensitivity analysis are consistent. After a study with heterogeneity is excluded, the heterogeneity disappears and the result remains stable.
Organ transplant was pooled from 3 studies with a significant (OR,1.96; 95%CI: 1.48-2.61), low heterogeneity(I2=0%). The results are still stable after using the random effects model.
5.Tests for Publication Bias
All risk factors (≥7 studies) of the egger’s rank correlation test and the Egger linear regression test indicated no evidence of publication bias except cardiovascular disease (P=0.015) (table3). Smoke history, cirrhosis, multiorgan dysfunction (≥3),unknow site of infection, vasoactive drugs, diuretics and organ transplant were not performed test of public bias because of less number of studies(<7 studies)