N-acetylcysteine for the prevention of contrast-induced nephropathy

OBJECTIVE: Contrast-induced nephropathy is a common cause of acute renal failure in hospitalized patients. Although patients are often given N-acetylcysteine to prevent renal injury from contrast agents, there are no clear guidelines supporting its use. We conducted a systematic review to determine whether administering N-acetylcysteine around the time of contrast administration reduces the risk of contrast-induced nephropathy. DESIGN: We searched MEDLINE, EMBASE, the Cochrane Collaboration Database, bibliographies of retrieved articles, and abstracts of conference proceedings, and consulted with experts to identify relevant studies. Randomized controlled trials of N-acetylcysteine in hospitalized patients receiving contrast were included. Studies were excluded if they did not report change in creatinine or incidence of contrast-induced nephropathy at 48 hours. MEASUREMENTS AND MAIN RESULTS: Nine randomized controlled trials satisfied all inclusion criteria and were included in the analysis. The difference in mean change in creatinine between the N-acetylcysteine-treated group and controls was -0.27 mg/dl (95% confidence interval [CI], -0.43 to -0.11). The relative risk of developing contrast-induced nephropathy was 0.43 (95% CI, 0.24 to 0.75) in subjects randomized to N-acetylcysteine. Significant heterogeneity existed among studies, suggesting differences in patient populations or study methodology not identified by sensitivity analyses. The incidence of dialysis was rare (0.2%). CONCLUSIONS: Our findings suggest that N-acetylcysteine helps prevent declining renal function and contrast-induced nephropathy. While N-acetylcysteine is inexpensive and nontoxic, undeviating insistence for dosing at least 12 hours in advance of contrast exposure may delay diagnostic and therapeutic procedures. Future studies are needed to address the longer-term clinical outcomes and cost-effectiveness of this agent.     

他汀类药物预防对比剂肾病的研究进展

对比剂肾病(CIN)是一种血管造影术中使用对比剂出现的严重并发症,它在常见的医院获得性急性肾损伤中居第三位。对比剂肾病的发病机理尚不完全清楚,一些研究发现他汀类药物对预防对比剂肾病具有重要意义。虽然在一些患者中需要使用透析治疗,但CIN的治疗主要为支持治疗,包括小心液体的输入和电解质纠正,因此,最佳的治疗就是预防为主。该文主要对CIN的流行病学、发病机理和他汀类药物预防作用及可能机制进行综述。     

Selective renal arterial infusion of fenoldopam for the prevention of contrast-induced nephropathy

Contrast-induced nephropathy (CIN) remains an important complication of angiographic procedures, particularly among patients with significant renal impairment. To date, vasodilator therapies such as fenoldopam have failed to prevent CIN, possibly because significant hypotension as a result of systemic infusion has limited the ability to deliver adequate drug levels to the renal vasculature. We present a case of averted CIN after multivessel coronary intervention in a diabetic patient with severe renal insufficiency, potentially due to bilateral renal arterial infusion of fenoldopam. Our subsequent experience with intrarenal fenoldopam in nine additional procedures in eight other high risk patients resulted in one case of asymptomatic transient CIN. Further studies are warranted to evaluate the efficacy of intrarenal administration of vasodilator therapies such as fenoldopam for the prevention of CIN.     

Prospective randomized study of N-acetylcysteine, fenoldopam, and saline for prevention of radiocontrast-induced nephropathy.

The objective of this study was to compare the efficacy of N-acetylcysteine (NAC), fenoldopam, and saline in preventing radiocontrast-induced nephropathy (RCIN) in high-risk patients undergoing cardiovascular procedures. We prospectively enrolled 123 patients who were scheduled for cardiovascular procedures and had a baseline creatinine > 1.6 mg/dl or creatinine clearance of < 60 ml/min. Patients were randomly assigned to receive either saline (0.45% normal saline at 1 cc/kg) for 12 hr before and 12 hr after the procedure, or fenoldopam (0.1 microg/kg/min) plus saline for 4 hr prior and 4 hr after the procedure, or NAC orally (600 mg) plus saline every 12 hr for 24 hr prior and 24 hr after the procedure. All the patients received low-osmolality nonionic contrast. RCIN was defined as an increase in creatinine level > 0.5 mg/dl after 48 hr. The incidence of RCIN was 17.7% in the NAC group, 15.3% in the saline group, and 15.7% in the fenoldopam group (P = 0.919). Of the 20 patients who developed RCIN, 2 required dialysis. Serum creatinine decreased after 48 hr (vs. baseline) in 38% patients in the NAC group, 18% in the fenoldopam group, and 15% in the saline group. In patients with chronic renal insufficiency, NAC or fenoldopam offered no additional benefit over hydration with saline in preventing RCIN.     

Prevention of contrast-induced nephropathy: A randomized controlled trial of sodium bicarbonate and N-acetylcysteine

BACKGROUND:

Contrast-induced nephropathy (CIN) continues to be a common cause of acute renal failure in high-risk patients undergoing radiocontrast studies. However, there is still a lack of consensus regarding the most effective measures to prevent CIN.

METHODS:

One hundred eighteen patients with diabetes mellitus and/or renal insufficiency, scheduled for coronary angiography or intervention, were randomly assigned to one of four treatment groups: intravenous (IV) 0.9% NaCl alone, IV 0.9% NaCl plus N-acetylcysteine (NAC), IV 0.9% sodium bicarbonate (NaHCO₃) alone or IV 0.9% NaHCO₃ plus NAC. All patients received IV hydration as a preprocedure bolus and as maintenance. Iso-osmolar contrast was used in all patients. CIN was defined as an increase of greater than 25% in the serum creatinine concentration from baseline to 72 h.

RESULTS:

The overall incidence of CIN was 6%. There was no statistically significant difference in the incidence of CIN among the groups. There was a CIN incidence of 7% in the NaCl only group, 5% in the NaCl/NAC group, 11% in the NaHCO₃ only group and 4% in the NaHCO₃/NAC group (P=0.86). The maximum increase in serum creatinine was 14.14±12.38 μmol/L in the NaHCO₃ group, 10.60±29.14 μmol/L in the NaCl only group, 9.72±13.26 μmol/L in the NaCl/NAC group and 0.177±15.91 μmol/L for the NaHCO₃/NAC group (P=0.0792).

CONCLUSION:

CIN in high-risk patients may be effectively minimized solely through the use of an aggressive hydration protocol and an iso-osmolar contrast agent. The addition of NaHCO₃ and/or NAC did not have an effect on the incidence of CIN.     

Effectiveness of theophylline in preventing contrast-induced nephropathy after coronary angiographic procedures

Background: Contrast‐induced nephropathy (CIN) is the third most common cause of hospital acquired acute renal failure and is associated with increased morbidity and mortality. The use of theophylline for prevention of CIN has yielded conflicting results. This study aimed at examining the effectiveness of theophylline in prevention of CIN when added to IV hydration and N‐acetylcysteine (NAC). Methods: Patients with stable serum creatinine and at least moderate risk for CIN according to Mehran's risk score were included in this parallel group, 1:1, single‐blind, randomized controlled trial. All patients received IV hydration (1 mL/kg per hour for 24 hours) and NAC (600 mg bid for 2 days). Patients were randomized to placebo (group P) or theophylline (200 mg in 100 mL 0.9% saline, as IV infusion 30 minutes before contrast medium (CM) administration; group T). Patients underwent standard coronary angiography ± angioplasty. Serum creatinine (SCr) was assessed just before and 72 hours after contrast administration and estimated glomerular filtration rate (eGFR) was calculated. Results: This study included 60 patients with mean SCr 1.44 ± 0.7 mg/dL and eGFR 60.2 ± 29.2 mL/min. Mean SCr among group T was 1.54 ± 0.7 mg/dL with eGFR 58.6 ± 28.6 mL/min, while group P showed mean SCr of 1.34 ± 0.7 mg/dL and eGFR of 61.8 ± 30.1 mL/min. Among group P, 6 (20%) patients developed CIN while none of the patients in group T developed CIN. In comparison to placebo, theophylline significantly decreased SCr (P = 0.0001) and increased eGFR (P = 0.001) at 72 hours. Multivariate regression analysis showed that receiving placebo instead of theophylline, anemia, congestive heart failure, chronic renal impairment, and high‐contrast load are all independent predictors for deteriorating renal function after CM administration. Conclusion: Theophylline seems to be an effective prophylaxis against CIN for moderate‐ and high‐risk patients undergoing coronary angiography or angioplasty. It offers additive protection when added to IV hydration and NAC. (J Interven Cardiol 2012;25:404–410)     

叉头转录因子O1在冬虫夏草预防糖尿病模型大鼠对比剂肾病中的机制

目的探讨叉头转录因子(Fox)O1在冬虫夏草预防糖尿病模型大鼠对比剂肾病中的机制。方法 SD大鼠80只,随机选取20只为正常对照组(N组),其余60只腹腔注射链脲佐菌素(60 mg/kg)建立糖尿病模型,造模成功后再随机分为对比剂肾病组(M组)、冬虫夏草组(D组)、普罗布考组(P组)。10 w后,N组和M组给予生理盐水灌胃,D组和P组分别给予冬虫夏草(3.0 g/kg)和普罗布考(500 mg/kg)灌胃。7 d后,麻醉状态下,除N组外,其他三组给予碘克沙醇320(2.0 g/kg)。取血标本测血清肌酐(Scr)、尿素氮(BUN),取尿标本测尿中性粒细胞明胶酶相关脂质运载蛋白(NGAL)、肾损伤因子(KIM)-1、白细胞介素(IL)-18;肾脏标本用于肾脏病理研究、氧化应激指标检测、蛋白激酶B(Akt)/哺乳动物雷帕霉素靶蛋白(mTOR)/P70核糖体蛋白S6激酶(P70S6K)通路及FoxO1的研究。结果与M组比较,D组Scr、BUN、NAGL、KIM-1、IL-18水平均明显降低(P<0.05),P组BUN、Scr、NAGL、IL-18含量明显降低(P<0.05),而KIM-1无明显变化(P>0.05)。与M组比较,D组丙二醛(MDA)含量明显降低,而一氧化氮(NO)、一氧化氮合酶(NOS)、超氧化物歧化酶(SOD)和总抗氧化能力(T-AOC)含量明显升高;P组MDA含量亦明显降低,NO、NOS和SOD含量明显升高(P<0.05),T-AOC无明显变化。与M组比较,D组和P组磷酸化(p-Akt)、p-mTOR、p-P70S6K mRNA及蛋白表达水平均明显升高,p-FoxO1 mRNA水平和蛋白表达明显降低,p-FoxO1/FoxO1比值显著降低。结论冬虫夏草可通过上调信号通路Akt/mTOR/P70S6K蛋白表达水平,进而促使FoxO1高表达,减少其磷酸化水平,减轻氧化应激和肾细胞凋亡,对糖尿病对比剂肾病大鼠的肾脏具有较好的保护作用。     

Abbreviated dosing of N-acetylcysteine prevents contrast-induced nephropathy after elective and urgent coronary angiography and intervention

BACKGROUND AND HYPOTHESIS: Several studies have utilized low-dose regimens of N-acetylcysteine (NAC) for 48 hours to prevent contrast-induced nephropathy (CIN) after cardiac catheterization (cath) and percutaneous coronary intervention (PCI). A lengthy pretreatment period with NAC may not be feasible in urgent situations. The purpose of this study was to assess the efficacy of an abbreviated, higher dose regimen of NAC for the prevention of CIN after elective and urgent coronary angiography (cath) and/or percutaneous coronary intervention (PCI). METHODS: We prospectively evaluated 80 patients referred for elective or urgent cath and/or PCI with stable chronic renal insufficiency (creatinine clearance <50 cc/min). Patients were randomized to: NAC 1000 mg PO 1 hour before cath/PCI and 4 hours later, or placebo. All patients received hydration (0.9% saline) before and after cath/PCI (minimum total volume > or = 1500 mL). CIN was defined as an increase of Cr > or = 0.5 mg/dL or > or = 25% 48 hours after cath/PCI. RESULTS: CIN occurred in 3 of 36 (8%) patients of the NAC group vs. 11 of 44 (25%) in the placebo group (P = 0.051; OR 3.7, 95% CI 0.94-14.4). Serum creatinine (mean +/- SD) remained stable in the NAC group after cath/PCI (2.02 +/- 0.56 vs. 2.10 +/- 0.81 mg/dL; P = 0.34), but increased after cath/PCI in the placebo group (1.93 +/- 0.53 vs. 2.10 +/- 0.74 mg/dL; P < 0.01). CONCLUSIONS: An abbreviated, higher dose regimen of NAC prevents the rise of serum creatinine 48 hours after cath/PCI, and may prevent CIN after cath/PCI.     

Role of N-acetylcysteine in prevention of contrast-induced nephropathy after cardiovascular procedures: a meta-analysis

BACKGROUND: Contrast-induced nephropathy is one of the common causes of acute renal insufficiency after cardiovascular procedures. HYPOTHESIS: The objective of this paper was to analyze the published data on the usefulness of N-acetylcysteine in the prevention of contrast-induced nephropathy after these procedures. METHODS: Trials were selected if they were prospective, randomized, controlled, had selected patients with impaired renal function, used low-osmolality, nonionic contrast media intra-arterially, administered a total of four doses of N-acetylcysteine in addition to intravenous saline hydration, and had contrast-induced nephropathy as their primary outcome. Contrast-induced nephropathy was defined as an increase in serum creatinine concentration by >0.5 mg/dl or a 25% increase above baseline at or within 48 h post procedure. Meta-analysis was performed using the Fisher's Combined Test with a measure of effect size. The magnitude of the N-acetylcysteine effect was estimated using random-effects models. Homogeneity was evaluated using the chi-square test of homogeneity and standard Q statistic. Reporting bias was explored by the Rosenthal method. RESULTS: The Fisher's Combined Test was significant at p < 0.005 in favor of N-acetylcysteine. The size of the N-acetylcysteine effect was to reduce contrast-induced nephropathy by 20%. There was a 62% relative risk reduction in contrast-induced nephropathy with N-acetylcysteine using a fixed-effects model, and a 70% relative risk reduction using the random-effects model. In addition, we found that 27 unpublished trials showing no effects of N-acetylcysteine would exist to overturn the combined significance of p < 0.005 of the five trials in our meta-analysis. CONCLUSION: Oral administration of N-acetylcysteine in addition to intravenous saline hydration has a beneficial effect in the prevention of contrast-induced nephropathy after cardiovascular procedures in patients with impaired renal function.     

N-乙酰半胱氨酸对老年冠心病患者介入治疗后造影剂肾病的预防作用

目的探讨N-乙酰半胱氨酸(NAC)对老年冠心病患者PCI后造影剂肾病的预防作用。方法前瞻性入选天津市胸科医院心内科择期行PCI术的老年冠心病患者300例,按照随机数字表法分为NAC治疗组(NAC组)150例,常规治疗组(常规组)150例。其中NAC组给予NAC+水化治疗,常规组给予单纯水化治疗。观察2组患者PCI术前及术后72h血肌酐、肌酐清除率、尿素、β2微球蛋白(β2-MG)、C反应蛋白(CRP)、白细胞介素6(IL-6)、TNF-α、谷胱甘肽过氧化物酶(GPX)、超氧化物歧化酶(SOD)水平的变化,分析2组患者造影剂肾病发病情况。结果 NAC组与常规组PCI术后造影剂肾病发病率差异无统计学意义(P>0.05)。与术前比较,PCI术后72h,2组CRP、SOD、GPX水平明显升高(P<0.05),而2组血肌酐、肌酐清除率、尿素、IL-6、β2-MG比较,差异无统计学意义(P>0.05)。与常规组比较,PCI术后72h,NAC组SOD、GPX、CPR水平明显降低(P<0.01);而2组血肌酐、肌酐清除率、尿素、IL-6、β2-MG水平比较,差异无统计学意义(P>0.05)。结论 NAC对老年冠心病患者PCI术后造影剂肾病可能无预防作用。     

Risk markers for contrast-induced nephropathy

Radiological procedures requiring intravascular administration of iodinated contrast media are becoming a common source of an iatrogenic disease known as contrast-induced nephropathy (CIN). The treatment of established CIN is limited to supportive measures and dialysis. Therefore, identifying high-risk patients is the first step to minimize the overall risk of CIN. The purpose of this review is to describe classic and possible risk markers of CIN according to the ultimate clinical research and developments. Original publications, review articles, papers from our personal library, and guidelines on CIN were reviewed. Terms used for PubMed and Medline searches were as follows: "contrast-induced nephropathy," "radio-contrast nephropathy," "contrast nephropathy," "contrast medium-induced nephropathy," "contrast media," and "risk factors." No restriction was placed on date of publication. Preexisting renal failure, especially when secondary to diabetic nephropathy, is the most important risk marker for CIN.     

造影剂肾病的预防

造影剂肾病是医院获得性急性肾衰竭的常见原因,但到目前为止,对已发生的造影剂肾病尚无有效治疗.本文就如何有效地预防造影剂肾病的发生作一综述.     

Pathophysiology of contrast-induced nephropathy

Contrast media induce various factors that may increase vasoconstriction and decrease vasodilatation in the renal medulla, leading to hypoxia and acute tubular necrosis known as contrast-induced nephropathy (CIN) that tends to occur in diabetics and patients with preexisting renal insufficiency. Contrast media inhibit mitochondrial enzyme activities and subsequently increase adenosine through hydrolysis of ATP. Both catabolism of adenosine and medullary hypoxia generate reactive oxygen species (ROS) that scavenge nitric oxide (NO). Released along with endothelin and prostaglandin from endothelial cells exposed to contrast media, adenosine activates the A1 receptor that mainly constricts afferent arteriole at the glomerulus but not the medullary vasculature. Adenosine also activates the A2 receptor that increases NO production, leading to medullary vasodilatation which is induced by activation of endothelin-B receptor and G-protein coupled E-prostanoid receptor 2, and 4 of prostaglandin PGE2 respectively as well. Conversely medullary vasoconstriction is mediated by activating endothelin-A receptor and G-protein coupled E-prostanoid receptor 1, and 3 of prostaglandin PGE2 respectively. The osmotic load of contrast media increases interstitial pressure and sodium transport and thus oxygen consumption. Risking hypoxia, increased medullary oxygen consumption may also result from stimulating Na(+)-K(+)-ATPase activity by endothelin-A receptor. N-acetylcysteine (NAC) scavenges ROS and therefore preserves NO that not only dilates medullary vasculature but also reduces sodium reabsorption and oxygen consumption, tipping the balance against medullary vasoconstriction, hypoxia, and thus CIN. While prostacyclin and its analog, iloprost, prevent CIN by inducing medullary vasodilatation, atrial natriuretic peptide (ANP) may do so by inhibiting renin secretion.     

Comparison of two hemofiltration protocols for prevention of contrast-induced nephropathy in high-risk patients

Purpose

Contrast-induced nephropathy is a complication of contrast medium administration during diagnostic and interventional procedures, with important prognostic relevance. Patients with chronic kidney disease have a higher risk for contrast-induced nephropathy and poorer outcome. In patients with chronic kidney disease, hemofiltration reduces contrast-induced nephropathy incidence and improves long-term survival. We assessed the mechanisms involved in the prophylactic effect of hemofiltration and of the most effective hemofiltration protocol to prevent contrast-induced nephropathy in patients with chronic kidney disease.

Subjects and methods

We randomized 92 patients with chronic kidney disease (creatinine clearance ≤30 mL/min) to three different prophylactic treatments: intravenous hydration with isotonic saline (1 mL · kg · h for 12 hours before and after contrast exposure, control group; n = 30); intravenous hydration for 12 hours before contrast exposure, followed by hemofiltration for 18 to 24 hours after contrast exposure (post-hemofiltration group; n = 31), and hemofiltration performed for 6 hours before and for 18 to 24 hours after contrast exposure (pre/post-hemofiltration group; n = 31). The incidence of contrast-induced nephropathy (>25% increase in creatinine) and the in-hospital clinical course were compared in the three groups.

Results

Twelve patients (40%) in the control group, 8 patients (26%) in the post-hemofiltration group, and 1 patient (3%) in the pre/post-hemofiltration group experienced contrast-induced nephropathy (P = .0013); hemodialysis was required in 9 (30%), three (10%), and zero (0%) patients, respectively (P = .002). In-hospital mortality was 20%, 10%, and 0%, respectively (P = .03).

Conclusions

Hemofiltration is an effective strategy for contrast-induced nephropathy prevention in patients with chronic kidney disease who are undergoing cardiovascular procedures. Pre-hemofiltration is required to obtain the full clinical benefit, suggesting that, among different mechanisms possibly involved, high-volume controlled hydration before contrast media exposure plays a major role.