Prevalence and predicting factors of acute kidney injury due to methanol intoxication; a systematic review

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Introduction
Methanol or methyl alcohol is an industrial substance with various uses, including automobile manufacturing, jet fuel, the perfume industry, copier fluids, antifreeze (1), laboratories (2), and washing fluid (3). Methyl alcohol is much cheaper than ethanol, and their morphological similarity encourages using methanol for making adulterate and illegal alcoholic beverages (3,4).
Methanol intoxication is a medical, social, and economic serious issue; severe intoxication is rare but has occurred in many cases and different countries (5). Since the beginning of the current century, methanol intoxication has caused many deaths and complication worldwide due to delays in diagnosis (4). Previous studies reported various complications of methanol poisoning, such as putaminal hemorrhage, metabolic acidosis, visual impairment (6), hypokalemia, renal failure, respiratory failure, neurological failure (7), troponin rising (8), hypothermia, hypotension, low consciousness (9), and acute kidney injury (AKI) (2,(8)(9)(10)(11). Furthermore, some of these studies reported that, among methanol poisoning complications, AKI is one of the most common and related factors to mortality and morbidity (2,9,11). In this study we determine how much AKI is common in methanol intoxication and what factors can predict it.

Objectives
The most rational reason for conducting this study is the lack of a study that evaluated AKI prevalence as a systematic review and reported its worldwide prevalence. This review study aimed to evaluate the prevalence of AKI due to methanol intoxication and its predicting factors.

Study design
This systematic review aimed to assess the prevalence of AKI due to methanol poisoning and to identify its predictors. To explore the relevant studies, we performed a search strategy using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist (12). The main question of this review study is the frequency of AKI in methanol poisoning and what factors influence its incidence.

Search strategy and studies selecting
Search libraries such as Cochrane and WorldCat and international databases, including Web of Science, Scopus, Pubmed, Ovid/Medline, Embase, Dimension, OpenGrey, EBSCO, DOAJ, CINAHL and Google scholar search engines, were used to find related studies. Standard keywords and using Medical Subject Headings (MeSH) were conducted for a complete search. Acute renal injury, acute renal failure, acute renal insufficiency, methanol intoxication, methanol poisoning, wood alcohol, carbinol, and methyl alcohol were applied as keywords in the search strategy. There were no time, language, and location limitations regarding this search strategy, and the search was upgraded until March 2023. Applied combination keywords included OR and AND. The following string shows PubMed search strategy protocol:

Eligibility criteria
Studies that evaluated the prevalence of AKI due to methanol intoxication were included in this study.

Exclusion criteria
Exclusion criteria included studies with missing required data, duplicates, full-text unavailable studies, studies of low quality, qualitatively assessed studies, studies with case reports, conference studies, and letter to editors' studies. Moreover, studies that evaluated the AKI prevalence in intoxicated patients with alcohols other than methanol, and studies that assessed methanol poisoning without reporting AKI prevalence were excluded.

Quality assessment of the studies
For each included study, a second reviewer investigated all extracted data during the study's quality assessment process. Two investigators independently evaluated the initial articles based on the STROBE (Strengthening The Reporting of OBservational Studies in Epidemiology) checklist for the observational studies. This checklist consists of 22 items covering different parts of the study. Each item has two points, and the total point was calculated by pooling these items. Therefore, values 1-15 indicate poor quality, 16-30 medium quality, and 31-4 4 highest quality. The cut-off point in our study was scored more than 15 (13). In case of disagreement, the third reviewer reassessed the article, and the discussion was resolved by reaching a consensus on a single option. It is noted that all included studies had good quality.

Data extraction
To avoid the risk of bias in data collection, two investigators, other than the individuals who searched the studies, independently extracted the required data using a checklist, including the authors' names, study design, publication year, country, mean age, male percent, study objective, sample size, frequency of AKI, and related factors to AKI. Data were re-evaluated by a third investigator in case of discrepancies.

Results
In the current systematic review research; studies that reported AKI prevalence after methanol intoxication were reviewed based on the PRISMA guideline. During the initial search, 905 articles were identified; Due to duplicate studies, 409 were removed. Out of the 496 remaining articles, 381 were excluded after the abstract review due to having no inclusion criteria. Out of the 115 remaining articles, 38 were not retrieved, and 77 were assessed for eligibility. Based on exclusion criteria, 71 articles were excluded, and six remained in the final analysis ( Figure 1).
Results demonstrated that six studies from five countries around the world, with a sample size of 816 methanol intoxication patients, were included in this study. The study by Thongprayoon et al (2) in the USA and the study by Salek et al (8) in the Czech republic were the biggest and smallest study in terms of sample size, with a sample size of 603 and 13 people respectively. Regarding study design, three were cohort, two cross-sectional, and one was case series. Most poisoning patients were male in all studies ( Table 1).
The prevalence of AKI in the study by Chang et al was the most (66%), and in the study by Salek et al was the lowest (15.4%) without considering the sample size. When we pooled all sample sizes in all studies and also pooled all patients with AKI and calculated AKI prevalence, AKI prevalence was 28.18% in all included studies (Table 1).

Discussion
In six studies with a population of 816 methanolintoxicated patients, 230 developed AKI (prevalence of 28.18%); Regardless of sample size, the lowest prevalence was 15.4%, and the highest was 66%. The most common AKI predictors were classified into three sections; gender male, hypertension, older age, anemia, and alcohol addiction regarding demographic characteristics; metabolic acidosis, high blood osmolality, and high formate concentration in terms of laboratories disorders; overdose state, sepsis, rhabdomyolysis, acute pancreatitis, and volume depletion in clinical findings.
In the study by Thongprayoon et al on 603 people, the prevalence of AKI was reported at 22.4%, and the most related factors were hypertension, anemia, volume depletion, sepsis, acute pancreatitis, and rhabdomyolysis. Considering the high sample size, this prevalence and also the reported AKI predictors can be trustable (2). The study by Salek et al had the lowest population (13 cases); in this study prevalence rate was 15.4%, and AKI predictors were not reported (8).
The second big study in terms of sample size was conducted on 93 intoxicated patients by Kumar et al in the Indian population. The prevalence of AKI in this study was reported at 27.9%, however AKI predictors were not reported (14). Male gender, alcohol addiction, alcohol overdose, and older age were reported by Chang et al as the most common risk factors for acute renal injury. In their cohort study, the prevalence of AKI was reported at 66% (11).
Lee et al in a nine-year cohort study stated that, out of 32 patients with methyl alcohol poisoning, AKI was found in 19 cases, which indicates a prevalence of 59.4%. Predicting factors for AKI were not reported in this study (9). Verhelst et al in a study in Belgium assessed 25 patients with methanol intoxication as a case series and reported greater blood osmolality, metabolic acidosis at baseline, and greater formate concentration as the most common predictor for acute renal injury; since the prevalence of AKI in this study was 60% (10).
Acute renal injury is an acute (less than 48 hours) decline in glomerular filtration rate (GFR) due to kidney injury that causes alterations in electrolyte and acid-base balance because of fluid and metabolic waste retention (15,16). Thus, AKI patients should be identified early and treated  immediately to reduce serious morbidity and death.

Conclusion
Knowing about the prevalence rate as well as identifying risk factors related to AKI in patients with methanol poisoning can help in their quick diagnosis, timely treatment, and reduce the subsequent complications especially reducing mortality.