Prevalence of contrast nephropathy following the administration of N-acetyl cysteine; a systematic review and meta-analysis

Introduction: Nephropathy is a serious complication in patients receiving contrast during imaging. N-acetyl cysteine (NAC) can reduce the contrast nephropathy. This review evaluates the prevalence of contrast-induced nephropathy (CIN) following the administration of NAC. Methods: A systematic literature search and meta-analysis was conducted in Scopus, Web of Science and PubMed for articles published by December 30, 2019 including the keywords of "N-acetyl cysteine ", "Acute kidney injury", "Nephrotoxicity", "Contrast media", "Contrast-induced AKI" and "Contrast nephropathy". Results: A total of 29 articles of 537 studies examining 5,980 individuals were incorporated in this systematic review and meta-analysis. Pooled estimation of a meta-analysis of prevalence studies reported a prevalence of 9% (0.09), i.e. nine out of every 100 patients undergoing contrast media resulted in CIN but a prevalence of 14% (0.14) was observed in the placebo group. In addition, 41 out of every 100 patients with hypertension undergoing contrast media resulted in CIN (prevalence: 41%) and 64 out of every 100 patients with diabetes undergoing contrast media resulted in CIN (prevalence: 64%). Conclusion: The prevalence of CIN in the group receiving NAC is lower than those who did not receive this drug. Additionally, in patients suffering from diabetes and hypertension, CIN is more prevalent compared to healthy people.


Introduction
The use of contrast agents in imaging exposes the kidneys to damage, which is called contrast-induced nephropathy (CIN). The term is used when serum creatinine more than 25% of baseline or more than 0.5 mg/ dL increases within 2-3 days after contrast administration, without the presence of other kidney diseases. The incidence of CIN in the adult population undergoing cardiac angiography is about 30% (1). Occurrence of CIN is of great importance because of its high mortality rate that is reported to be as high as 34% (2). Contrast agents are one of the most important causes of damage to renal tubules and acute tubular necrosis. Risk factors for nephropathy due to contrast agents include diabetes, chronic renal failure, severe congestive heart failure, fluid loss, hypotension, type and volume of contrast medium (3). Nephropathy due to contrast agents is the third most common cause of acute renal failure followed by low blood pressure and surgery in the hospital (4). People with a history of kidney failure, especially kidney damage due to diabetes, congestive heart failure, low blood pressure, high levels of contrast agents and concomitant use of drugs that impair kidney function, are at higher risk (5). Various substances have been tested in various studies to prevent harmful effects of contrast agents on the kidney including N-acetyl cysteine (NAC), theophylline, sodium bicarbonate, as c orbic acid, and diuretics (6). There are some metaanalyses regarding the effectiveness of NAC to prevent CIN. For example, a study by Sharp et al in 2019 (7), but another metaanalysis conducted by Li et al in 2017 showed that NAC therapy is not effective to prevent CIN in patients following angioplast y as a preventive treatment (8).

Key point
In a systematic literature search and meta-analysis, we found the prevalence of contrast nephropathy in the group receiving N-acetyl cysteine is lower than those who did not receive this drug. Additionally, in the patients suffering from diabetes and hypertension, contrast nephropathy is more prevalent compared to healthy people.

Eligibility criteria
Two of the authors independently evaluated the eligibility of the papers according to the PRISMA guidelines. Inclusion criteria were studies in English about nephropathy after contrast medium receiving in patients who received NAC as intervention in original studies, case series or case reports, but only original and case series were added in the meta-analysis. Exclusion criteria were studies done on animals. A structured checklist was used for the data extraction  including, type of study, patients numbers, age,  nephropathy (number, %), comorbidity, gender, NAC dose and complications. The data were retrieved by two independent investigators. The differences observed in this process were corrected by a third investigator independent from the other two. The Newcastle Ottawa Quality Assessment Scale (NOS) was used for qualitative assessment of studies (10).

Statistical analysis
The main measure of effect/effect size was prevalence (ratio of case to total population). Cochran's test (Q-test) (showing significant heterogeneity in the meta-analysis) and I2 (showing the amount of heterogeneity ranged from 0% to 100 %.) were used to assess the heterogeneity among the studies. The random-effects model was used for the continuous and frequency outcome under study. Additionally, a random effects meta-analysis was applied for estimating the main index, which was the pooled prevalence, at 95% confidence interval. A forest plot was used to present the pooled prevalence. Publication bias was assessed using Begg's tests. The analysis was performed using Stats version 13.

Results
A total of 29 articles of 537 studies examining 5980 patients were included in this systematic review and meta-analysis ( Figure 1). Study characteristics of the patients included in the meta-analysis are presented in Table 1.

Descriptive characteristics
The mean age of the participated individuals was 63.57 ± 9.18 years. The mean serum creatinine, BUN and creatinine clearance and additionally glomerular filtration rate (GFR) levels in the patients undergoing contrast media were 1.23 mg/dL, 30.65 mg/dL, 45.10 mL/min and 93.30 ml/min (Table 2). Regarding the dose of NAC administered in the prevention of CIN, the most common dose was 600 mg twice daily by two days (Figure 2).

Prevalence of CIN in the intervention groups
Pooled estimation of a meta-analysis of prevalence studies reported a prevalence of 9% (0.09), i.e. nine out of every 100 patients undergoing contrast media with NAC resulted in CIN (Figure 3).

Prevalence of CIN in the placebo groups
Pooled estimation of a meta-analysis of prevalence studies reported a prevalence of 14% (0.14), i.e. 14 out of every 100 patients undergoing contrast media without NAC resulted in CIN (Figure 4).

Prevalence of diabetes in the patients who developed CIN
Pooled estimation of a meta-analysis of prevalence studies reported a prevalence of 64% (0.64), i.e. 64 out of every 100 patients with diabetes undergoing contrast media resulted in CIN ( Figure 5).

Prevalence of hypertension in the patients who developed CIN
Pooled estimation of a meta-analysis of prevalence studies reported a prevalence of 41% (0.41), i.e. 41 out of every 100 patients with hypertension undergoing contrast media resulted in CIN ( Figure 6).

Publication bias
The results of the analysis showed that bias publication did not have an influence on the creation of negative results, which is shown as symmetry in the funnel plot. Meanwhile, no evidence of publication bias was detected using Egger's test (Egger's test t = 2.84, P = 0.014, 95% CI: 2.207 to 16.206).

Discussion
This review showed that the prevalence of CIN in the group receiving NAC is lower than those did not receive NAC (placebo). In addition, CIN in the patients suffering from diabetes (64%) and hypertension (41%) is prevalent compared to healthy people. In a study by Ala et al, investigated the effects of N-acetylcysteine in preventing CIN due to coronary angiography in patients with normal renal function. They showed in the first group, fluids with oral NAC 600 mg twice daily for 2 days (the day before and the day of administration of contrast agent) and in the second group (control group), only fluids were prescribed. CIN was observed in 30 patients, 11 patients (22%) in the NAC group and 19 patients (38%) in the control group, and there was no significant difference. In the control group, the mean serum creatinine of patients increased significantly after 48 hours, but in the NAC group, no significant increase was observed in the mean serum creatinine of patients. These results suggest that AC has been able to reduce contrast-induced renal impairment (11). In a study conducted by Vallero et al in 2002 in Italy on 100 patients undergoing angiography with an iodixanol with a volume of 203 ml from 1-2 hours before to 24 hours after angiography and the NAC group received 600 mg twice daily before and immediately after angiography. Vallero et al showed no potential advantage of NAC in the prevention of acute nephropathy, induced by high volumes of contrast agent (12). The study by Hoffmann et al conducted on 50 patients with healthy renal function under contrast-enhanced angiography. In their investigation, serum creatinine was measured 48 hours after angiography, which showed a significant decrease in the group that received NAC. This study confirmed the effect of NAC in preventing renal impairment of contrast   agents in patients with healthy renal function undergoing angiography (14). There is strong controversy about the effectiveness of the NAC. In this regard, Loomba et al showed that NAC may not have any significant effect on clinical outcomes after cardiac catheterization (40). According to the results of a meta-analysis performed by Ali-Hassan-Sayegh et al in 2017, many procedures can be considered to prevent CIN in the patients undergoing angiography such as enough hydration, use of NAC and ascorbic acid (41). Our review approved the effect of NAC in preventing CIN compared to the placebo group in which in patients receiving NAC, the prevalence of CIN was 9% while it was 14% in the control groups. It should be noted that comorbidities can affect the prevalence of CIN, which our review indicated more frequency of hypertension and diabetes among patients with CIN. We showed, 41 out of every 100 patients with hypertension undergoing contrast media resulted in CIN (prevalence: 41%) and 64 out of every 100 patients with diabetes undergoing contrast media resulted in CIN (prevalence: 64%). These values are threatening the life of patients and it is recommended