Efficacy of Alprostadil in Preventing Contrast-Induced Nephropathy: A Systematic Review and Meta-Analysis

Abstract

This study aimed to determine the efficacy of alprostadil in preventing contrast-induced nephropathy (CIN). Eligible studies were searched using the keywords through the databases of PubMed, Cochrane, Embase, China Biological Medicine Database, China National Knowledge Infrastructure, and Vanfun. Quality evaluation of the included studies was conducted according to international evidence evaluation and recommended Grades of Recommendations Assessment, Development, and Evaluation standards. We included 29 studies with 5623 patients. Compared with hydration, 10 µg/d alprostadil or 20 µg/d alprostadil plus hydration significantly decreased the incidence of CIN. Compared with hydration, alprostadil plus hydration significantly reduced serum creatinine and blood urea nitrogen at 24, 48, and 72 hours and 7 days after coronary angiography (CAG). Alprostadil (20 µg/d) plus hydration significantly decreased serum cystatin versus hydration at 24, 48, and 72 hours after CAG. Compared with hydration, alprostadil plus hydration significantly increased glomerular filtration rate at 24 and 72 hours after CAG. Alprostadil plus hydration significantly decreased neutrophil gelatinase-associated lipocalin levels compared to hydration at 24, 48, and 72 hours after CAG. Alprostadil plus hydration significantly decreased urine macroglobulin versus hydration at 24 and 48 hours after CAG.

Keywords

alprostadil contrast-induced nephropathy meta-analysis

Introduction

Coronary angiography (CAG) or percutaneous coronary intervention (PCI) plays an important role in the treatment of coronary heart disease, and the use of contrast agents during CAG or PCI has significantly increased the incidence of renal impairment.¹ Clinically, contrast-induced nephropathy (CIN) refers to the sudden decline in renal function, probably caused by the contrast agent.² The diagnostic criteria is an increase in serum creatinine (Scr) at 48 hours after contrast administration, which is >44.2 pmol/L (0.5 mg/dL) or >25% above the baseline value; other causes of renal damage need to be excluded.¹

Renal excretion or metabolic dysfunction will lead to varying degrees of water, electrolyte, and acid–base balance disorders.^2,3 Therefore, in CIN patients with severely impaired renal function, water and sodium retention can aggravate heart failure after CAG or PCI. Renal dysfunction may lead to drug accumulation, thus increasing the incidence of postoperative bleeding and arrhythmias. In the long term, there will be multiple organ failure (eg, cardiovascular system, respiratory system, and digestive system).^1,4 Therefore, CIN has become one of the important problems affecting the short- and long-term outcomes of PCI. According to the studies,^5,6 the incidence of CIN is 0.62% in the general population after contrast medium and 3.3% to 14.4% after interventional therapy for cardiovascular disease. In combination with renal insufficiency, the incidence of CIN can be as high as 37%.

At present, there is no effective treatment for CIN, which mainly focuses on prevention. The preventive measures are mainly based on the pathophysiological basis of CIN. Hydration is considered standard preventive measure for CIN and is widely used in clinical practice because of its effectiveness, safety, and low cost.^5,6 However, the optimal way, amount, and time of hydration are still unclear. Treatments to prevent CIN also include sodium bicarbonate, N-acetylcysteine, vitamin C, diuretics, statins, dopamine, calcium channel blockers, endothelin receptor blockers, theophylline, adenosine receptor antagonists, antioxidants, and so on.^5,6 Based on reviewing eligible randomized controlled trials (RCTs), the aim of this study was to explore the efficacy of alprostadil in preventing CIN.

Methods

Search Strategy

The data of clinical indexes about alprostadil in preventing CIN were obtained from the included studies. In the databases (Cochrane, PubMed, Embase, China Biological Medicine Database, China National Knowledge Infrastructure, and Vanfun), all the relevant RCTs before November 2020 were reviewed. In the eligible RCTs, the references were also reviewed. The keywords included alprostadil, alprostadil injection, alteplase, prostaglandin E₁, PGE₁, contrast-induced nephropathy, CIN, coronary angiography, CAG, percutaneous coronary intervention, PCI, random, randomized control study, randomized controlled trial, and RCT. All the above keywords were combined with “AND” or “OR.” Literature retrieval was done by 2 investigators (C.Z. and J.X.) independently. However, when there was disagreement, a third investigator (N.H.) was involved to make a decision.

Following the PICOS (participants, interventions, comparison/outcome, study design) principle, the key search terms included (P, participants) patients undergoing CAG or PCI; (I, interventions) patients in the treatment group received alprostadil plus hydration while patients in the control group were treated by hydration; (C/O, comparison/outcome) the comparison of the related indexes; and (S, study design) RCT.

Study Selection Criteria

The included studies should meet all the following criteria: (1) The study was designed as an RCT, (2) the participants were undergoing CAG or PCI, (3) patients were treated by alprostadil and/or hydration, and (4) articles were written in English or Chinese.

If a study met one of the following criteria, it was excluded (1) duplicate articles or similar results; (2) data in the articles showed clear errors; (3) cohort study, case–control, case analysis, theoretical research or reviews, guideline, reports, meta-analyses, or other forms of research or comments that were not designed as an RCT; and (4) irrelevant outcomes.

The studies were reviewed by 2 investigators (X.T. and J.X.) independently to determine whether the included studies met the inclusion criteria. A third investigator (Z.Z.) was involved when there was any disagreement.

Data Extraction and Quality Assessment

In all the included RCTs, 2 categories of data (the basic characteristics of articles and the data of main clinical indexes) were extracted. The basic characteristics of articles included author names, year of publication, detailed interventions of alprostadil, sample size, age. and gender. The main clinical indexes included CIN, Scr, serum cystatin (CysC), neutrophil gelatinase-associated lipocalin (NGAL), glomerular filtration rate (GFR), blood urea nitrogen (BUN), urine macroglobulin (MG), and adverse event (AE). Data were extracted by 2 investigators (C.Z. and J.X.) independently. However, when there was disagreement, a third investigator (N.H.) was involved to make a decision.

Grades of Recommendations Assessment, Development, and Evaluation Evidence Quality Evaluation

Internationally recognized and recommended Grades of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality assessment methods were used to evaluate the meta-analysis results of alprostadil in preventing CIN.⁷ The evaluation considered whether the quality of the evidence was reduced by 5 factors: risk of bias, indirectness, inconsistency, inaccuracy, and publication bias.

Statistical Analysis

The STATA, version 10.0, was used to conduct all the data analysis. The heterogeneity of the included RCTs was assessed by χ² and I² tests, and the fixed-effect or random-effect models were selected by the above results. When the included RCTs were of high heterogeneity (χ² P ≤ .05 and an I² > 50%), we selected the random-effect model to analyze the indexes. When the included RCTs were of acceptable heterogeneity (χ² P > .05 and an I² ≤ 50%), we selected the fixed-effect model to analyze the indexes. Continuous variables were expressed as mean ± SD and analyzed by weighted mean difference (WMD). Categorical variables were expressed as percentages and analyzed by RR. Both CIN and AEs were analyzed by RR, while other indexes were analyzed by WMD. The multiple complementary methods (funnel plots, Begg and Mazumdar rank test, Egger test, and sensitive analysis) were used to access study quality and risk of bias.

Results

Overview of the Included Studies

A total of 752 articles were identified through initial search by initial keywords. After we reviewed the titles and abstracts, 656 articles were excluded. The remaining 96 articles were evaluated by reading the full text, and 7 articles were excluded by the selection criteria. The studies were excluded for the following reasons: Studies does not meet the selection criteria (n = 32), lack of clinical outcomes (n = 27), and review or theory research (n = 8). Finally, 29 studies^8–36 incorporating 5623 patients met the inclusion criteria and were included in this meta-analysis. The article screening process is presented in Figure 1. Based on the GRADE, we assessed the bias risks of the included 29 RCTs (Figure 2). The concealment of allocation in 17 studies were unclear, the outcome evaluator blinding method in 21 studies were unclear, and the other aspects were low risk.

The basic information of each study is summarized in Table 1. According to the dose of alprostadil, we divided the studies into 4 subgroups for analysis as follows: 10, 20, and 40 µg/d and others (10/20/40 ng/kg/min for 6 hours) (Tables 2 -5). Then, according to the index sampling time, we firstly divided the studies into 5 subgroups for analysis as follows: 12, 24, 48, and 72 hours and 7 days in patients undergoing CAG or PCI.

Table 1.

Basic Characteristics Description of Included Studies.

Study	Disease	Number of patients		Age (years)		Gender (M: male)
Study	Disease	T	C	T	C	T	C
Liu Wei-Jing, 2013⁸	20 µg/d	76	80	66.3	65.4	45M	49M
Li Wen-Hua, 2014⁹	20 ng/kg/min for 6 hours	82	81	64.71	63.63	57M	52M
Liang Min, 2018¹⁰	20 µg/d	240	240	62.8	62.18	153M	158M
Miao Ya, 2013¹¹	20 µg/d	154	176	79.08	78.26	120M	133M
Wang Jing, 2017¹²	10 µg/d	227	224	65	64	156M	155M
Xu Rong-He, 2013¹³	20 µg/d	35	28	70	69	26M	19M
Yang Shi-Cheng, 2018¹⁴	20 µg/d	150	150	67.8	67.8	112M	108M
Jens-Albrecht Koch, 2000a	10 ng/kg/min for 6 hours	32	29	67.8	64.2	21M	18M
Jens-Albrecht Koch, 2000b	20 ng/kg/min for 6 hours	33	29	68.9	64.2	27M	18M
Jens-Albrecht Koch, 2000c	40 ng/kg/min for 6 hours	23	29	68.2	64.2	11M	18M
Dai Meng, 2012¹⁶	10 µg/d	62	58	58.2	58.2	83M
Wang Lin, 2016¹⁷	20 µg/d	50	50	60.48	60.5	31M	32M
Wang Jing, 2014¹⁸	10 µg/d	77	81	66.2	65.2	47M	50M
Zhou Dong-Chi, 2013¹⁹	20 µg/d	112	103	62.1	63.2	65M	61M
Cui Jin, 2012²⁰	10 µg/d	51	48	61	62	33M	31M
Chen Long-Jin, 2017²¹	20 µg/d	70	60	57.7	57.6	44M	41M
Liu Wei-Jing, 2012a	10 µg/d	34	28	64.86	63.01	–	–
Liu Wei-Jing, 2012b	20 µg/d	34	28	66.7	63.01	–	–
Liu Wei-Jing, 2012c	40 µg/d	34	28	64.03	63.01	–	–
Li Yong-Hui, 2018²³	20 µg/d	30	30	61-73	62-75	16M	17M
Li Wen-Yuan, 2019²⁴	20 µg/d	220	220	67.82	66.83	144M	142M
Li Jia-Zheng, 2016²⁵	10 µg/d	50	53	56.84	58.11	33M	34M
Ban Xian-Yang, 2015²⁶	10 µg/d	35	35	68.9	71.2	19M	23M
Su Chen, 2015²⁷	10 µg/d	55	51	63.5	62.7	35M	23M
Wu Ying, 2016²⁸	10 µg/d	123	122	58.2	58	62M	62M
Ye Yun, 2006²⁹	20 µg/d	28	30	70.28	72.62	25M	26M
Xu Rong, 2012³⁰	10 µg/d	30	30	60	60	13M	12M
Zheng Jian-Wu, 2015³¹	10 µg/d	164	164	68.84	65.84	103M	99M
Ma Na, 2019³²	20 µg/d	321	320	72.33	71.88	184M	191M
Xu Rong-He, 2012³³	20 µg/d	35	28	70	69	26M	19M
Wang Ling-Qing, 2019³⁴	10 µg/d	85	80	70	69	57M	51M
Cai Qin-Hong, 2014³⁵	20 µg/d	50	50	53.8	53.1	36M	37M
Liu Yi, 2011³⁶	20 µg/d	29	29	57	59.4	16M	19M

Contrast-Induced Nephropathy

Table 2.

Results of Others Indexes in the Subgroups Analysis of 10 µg/d.

Index	N (case/control)	Time	WMD (95% CI)	P ^a	I² (%)	P ^b,c	P value
Index	N (case/control)	Time	WMD (95% CI)	P ^a	I² (%)	P ^b,c	Begg	Egger
Scr (µmol/L)	615/613	24 hours	−9.912 (−24.354 to 4.530)	<.001	98.1	.179	.174	.909
	584/565	48 hours	−15.881 (−25.330 to −6.433)	<.001	97.6	.001	.266	.241
	580/572	72 hours	−17.867 (−33.090 to −2.644)	<0.001	98.4	.021	.764	.800
	85/76	7 days	−17.472 (−32.041 to −2.902)	.161	49.0	.019	.999	–
NGAL (µg/L)	123/122	24 hours	−15.800 (−18.117 to −13.483)	–	–	<.001	–	–
	123/122	48 hours	−12.100 (−13.479 to −10.721)	–	–	<.001	–	–
GFR (mL/min/1.73 m²)	265/268	24 hours	4.684 (0.249 to 9.119)	.049	61.9	.038	.734	.108
	188/187	48 hours	2.612 (−1.120 to 6.344)	.008	79.1	.170	.999	.277
	394/391	72 hours	2.092 (−2.314 to 6.498)	.025	67.9	.352	.734	.728
BUN (mmol/L)	200/203	24 hours	−0.956 (−1.385 to −0.528)	.196	40.2	<.001	.999	–
	157/150	48 hours	−0.871 (−1.337 to −0.404)	.617	0.0	<.001	.999	–
	132/132	72 hours	−1.253 (−1.966 to −0.541)	.336	0.0	.001	.999	–
	34/28	7 days	−1.070 (−2.757 to 0.617)	–	–	.214	–	–
MG (μg/L)	50/53	24 hours	−220.000 (−465.029 to 25.029)	–	–	.078	–	–
	34/28	48 hours	−18.000 (−203.266 to 167.266)	–	–	.849	–	–
	50/53	72 hours	−240.000 (−489.002 to 9.002)	–	–	.059	–	–
	34/28	7 days	−32.100 (−214.909 to 150.709)	–	–	.731	–	–

Abbreviations: BUN, blood urea nitrogen; CysC, serum cystatin; GFR, glomerular filtration rate; MG, urine macroglobulin; NGAL, neutrophil gelatinase-associated lipocalin; Scr, serum creatinine; WMD, weighted mean difference.

^a P value of heterogeneity χ².

^b P value of pooled statistic.

^cBold represents P value is less than .05.

Table 3.

Results of Others Indexes in the Subgroups Analysis of 20 µg/d.

Index	n (case/control)	Time	WMD (95% CI)	P ^a	I² (%)	P ^b,c	P value
Index	n (case/control)	Time	WMD (95% CI)	P ^a	I² (%)	P ^b,c	Begg	Egger
Scr (µmol/L)	420/422	24 hours	−5.754 (−12.016 to 0.508)	<.001	79.3	.072	.851	.002
	1152/1159	48 hours	−11.043 (−17.272 to −4.814)	<.001	87.3	.001	.016	.005
	1551/1554	72 hours	−6.730 (−9.725 to −3.734)	<.001	86.4	<.001	.067	.157
	113/107	7 days	−29.337 (−56.256 to −2.417)	.011	77.9	.033	.296	.255
CysC (mg/L)	230/256	24 hours	−0.094 (−0.158 to −0.030)	.880	0.0	.004	.999	–
	701/726	48 hours	−0.422 (−0.748 to −0.095)	<.001	93.4	.011	.734	.267
	921/946	72 hours	−0.292 (−0.501 to −0.083)	<.001	95.2	.006	.086	.041
NGAL (µg/L)	76/80	24 hours	−13.200 (−20.319 to −6.081)	–	–	<.001	–	–
	76/80	48 hours	−7.260 (−12.744 to −1.776)	–	–	.009	–	–
	296/300	72 hours	−2.805 (−4.363 to −1.247)	.365	.000	<.001	.999	–
GFR (mL/min/1.73 m²)	70/60	24 hours	4.540 (3.991 to 5.089)	–	–	<.001	–	–
	240/240	48 hours	1.360 (−2.716 to 5.436)	–	–	.513	–	–
	580/570	72 hours	2.447 (−0.385 to 5.280)	.065	58.4	.090	.734	.355
BUN (mmol/L)	120/110	24 hours	−0.448 (−1.780 to 0.883)	.026	79.9	.509	.999	–
	612/607	48 hours	−1.119 (−1.848 to −0.390)	<.001	84.8	.003	.024	.010
	1011/1002	72 hours	−1.360 (−2.056 to −0.664)	<.001	94.0	<.001	.210	.112
	113/107	7 days	−1.321 (−2.445 to −0.196)	.109	54.9	.021	.999	.512
MG (μg/L)	50/50	24 hours	14.640 (−13.401 to 42.681)	–	–	.306	–	–
	84/78	48 hours	−43.005 (−73.933 to −12.077)	.841	0.0	.006	.999	–
	143/143	72 hours	−32.661 (−64.853 to −0.470)	.119	53.1	.047	.999	.612
	84/78	7 days	0.556 (−28.055 to 29.168)	.886	0.0	.970	.999	–

^a P value of heterogeneity χ².

^b P value of pooled statistic.

^cBold represents P value is less than .05.

Table 4.

Results of Others Indexes in the Subgroups Analysis of 40 µg/d.

Index	n (case/control)	Time	WMD (95% CI)	P ^a	I ²	P ^b,c	P value
Index	n (case/control)	Time	WMD (95% CI)	P ^a	I ²	P ^b,c	Begg	Egger
Scr (µmol/L)	34/28	48 hours	−23.890 (−53.246 to 5.466)	–	–	.111	–	–
	34/28	7 days	−26.380 (−50.092 to −2.668)	–	–	.029	–	–
BUN (mmol/L)	34/28	48 hours	−0.100 (−2.038 to 1.838)	–	–	.919	–	–
	34/28	7 days	−1.330 (−2.888 to 0.228)	–	–	.094	–	–
MG (μg/L)	34/28	48 hours	17.500 (−169.762 to 204.762)	–	–	.855	–	–
	34/28	7 days	14.100 (−171.800 to 200.000)	–	–	.882	–	–

Abbreviations: BUN, blood urea nitrogen; MG, urine macroglobulin; Scr, serum creatinine; WMD, weighted mean difference.

^a P value of heterogeneity χ².

^b P value of pooled statistic.

^cBold represents P value is less than .05.

Table 5.

Results of Others Indexes in the Subgroups Analysis of Others (10/20/40 ng/kg/min for 6 hours).

Index	n (case/control)	Time (hour)	WMD (95% CI)	P ^a	I² (%)	P ^b,c	P value
Index	n (case/control)	Time (hour)	WMD (95% CI)	P ^a	I² (%)	P ^b,c	Begg	Egger
Scr (µmol/L)	170/168	12	−0.106 (−0.194 to −0.019)	.834	0.0	.017	.734	.790
	170/168	24	−0.256 (−0.405 to −0.107)	.718	0.0	.001	.734	.065
	170/168	48	−0.492 (−0.764 to −0.221)	.649	0.0	<.001	.734	.122
NGAL (µg/L)	82/81	12	−11.730 (−19.635 to −3.825)	–	–	.004	–	–
	82/81	24	−2.990 (−5.648 to −0.332)	–	–	.027	–	–
	82/81	48	0.290 (−1.504 to 2.084)	–	–	.751	–	–
GFR (mL/min/1.73 m²)	82/81	12	1.590 (−4.347 to 7.527)	–	–	.600	–	–
	82/81	24	1.020 (−4.847 to 6.887)	–	–	.733	–	–
	82/81	48	1.730 (−4.309 to 7.769)	–	–	.574	–	–

Abbreviations: GFR, glomerular filtration rate; NGAL, neutrophil gelatinase-associated lipocalin; Scr, serum creatinine; WMD, weighted mean difference.^a P value of heterogeneity χ².

^b P value of pooled statistic.

^cBold represents P value is less than .05.

Compared with hydration, 10 and 20 µg/d alprostadil plus hydration significantly decreased the incidence of CIN (RR: 0.391, 95% CI, 0.285-0.536 and RR: 0.405, 95% CI, 0.317-0.518, respectively). However, there was no significant difference in the incidence of CIN between patients receiving 40 µg/d alprostadil plus hydration and patients receiving hydration (RR: 1.647, 95% CI, 0.425-6.388). There was no significant difference in the incidence of CIN between the other dose groups of alprostadil plus hydration and hydration (RR: 0.988, 95% CI, 0.205-4.751), and this may be related to only 2 studies included in this analysis. The above results are presented in Figure 3.

We carried out a sensitivity analysis of CIN and filled funnel plot with pseudo 95% confidence limits. From Figures 4 and 5, no studies were found to have a significant effect on the results, which were generally stable.

Adverse Events

Compared with hydration, 20 µg/d alprostadil plus hydration significantly decreased the incidence of AEs (RR: 0.502, 95% CI, 0.307-0.820). However, there was no significant difference in the incidence of AEs between patients receiving 40 µg/d alprostadil plus hydration and patients receiving hydration (RR: 0.142, 95% CI, 0.018-1.135). The above results are presented in Figure 6.

Other Indexes in the Subgroup Analysis of 10 µg/d Alprostadil

Compared with hydration, 10 µg/d alprostadil plus hydration significantly decreased Scr at 48 hours (WMD: −15.881, 95% CI, −25.330 to −6.433), 72 hours (WMD: −17.867, 95% CI, −33.090 to −2.644), and 7 days (WMD: −17.472, 95% CI, −32.041 to −2.902). Compared with hydration, 10 µg/d alprostadil plus hydration significantly decreased NGAL at 24 (WMD: −15.800, 95% CI, −18.117 to −13.483) and 48 hours (WMD: −12.100, 95% CI, −13.479 to −10.721). Compared with hydration, 10 µg/d alprostadil plus hydration significantly decreased BUN at 24 (WMD: −0.956, 95% CI, −1.385 to −0.528), 48 (WMD: −0.871, 95% CI, −1.337 to −0.404), and 72 hours (WMD: −1.253, 95% CI, −1.966 to −0.541). There was no significant difference of GFR and urine MG between hydration and 10 µg/d alprostadil plus hydration.

Other Indexes in the Subgroup Analysis of 20 µg/d Alprostadil

Compared with hydration, 20 µg/d alprostadil plus hydration significantly decreased Scr at 48 hours (WMD: −11.043, 95% CI, −17.272 to −4.814), 72 hours (WMD: −6.730, 95% CI, −9.725 to −3.734), and 7 days (WMD: −29.337, 95% CI, −56.256 to −2.417). Compared with hydration, 20 µg/d alprostadil plus hydration significantly decreased CysC at 24 (WMD: −0.094, 95% CI, −0.158 to −0.030), 48 (WMD: −0.422, 95% CI, −0.748 to −0.095), and 72 hours (WMD: −0.292, 95% CI, −0.501 to −0.083). Compared with hydration, 20 µg/d alprostadil plus hydration significantly decreased NGAL at 24 (WMD: −13.200, 95% CI, −20.319 to −6.081), 48 (WMD: −7.260, 95% CI, −12.744 to −1.776), and 72 hours (WMD: −2.805, 95% CI, −4.363 to −1.247). Compared with hydration, 20 µg/d alprostadil plus hydration significantly decreased BUN at 48 hours (WMD: −1.119, 95% CI, −1.848 to −0.390), 72 hours (WMD: −1.360, 95% CI, −2.056 to −0.664), and 7 days (WMD: −1.321, 95% CI, −2.445 to −0.196). Compared with hydration, 20 µg/d alprostadil plus hydration significantly decreased MG at 48 (WMD: −43.005, 95% CI, −73.933 to −12.077) and 72 hours (WMD: −32.661, 95% CI, −64.853 to −0.470).

Other Indexes in the Subgroup Analysis of 40 µg/d Alprostadil

Compared with hydration, 40 µg/d alprostadil plus hydration significantly decreased Scr at 7 days (WMD: −26.380, 95% CI, −50.092 to −2.668). There was no significant difference of BUN and MG between hydration and 40 µg/d alprostadil plus hydration.

Other Indexes in the Subgroups Analysis of Others (10/20/40 ng/kg/min for 6 hours)

Compared with hydration, other doses of alprostadil plus hydration significantly decreased Scr at 12 (WMD: −0.106, 95% CI, −0.194 to −0.019), 24 (WMD: −0.256, 95% CI, −0.405 to −0.107), and 48 hours (WMD: −0.492, 95% CI, −0.764 to −0.221). Compared with hydration, other doses of alprostadil plus hydration significantly decreased NGAL at 12 (WMD: −11.730, 95% CI, −19.635 to −3.825) and 24 hours (WMD: −2.990, 95% CI, −5.648 to −0.332). There was no significant difference in GFR between hydration and other doses of alprostadil plus hydration.

Quality and Bias Assessment

Multiple complementary methods (funnel plots, Begg and Mazumdar rank test, and Egger test) were used to assess study quality and risk of bias. The funnel plot was based on the log RR funnel plot for CIN for all the studies (Figure 7) and showed a clear symmetry, indicating a low publication bias. Besides, there still was no significant bias risk in the included studies by Begg and Mazumdar rank test (Z = 1.18, P = .237) and Egger test (P = .262).

Discussion

The pathogenesis of CIN has not yet been clarified, and current studies have suggested at least the following 5 mechanisms: (1) direct damage by contrast agent to renal tubular epithelial cells: The contrast agent can be freely filtered and not absorbed, leading to increased osmotic pressure in the renal tubules. The hyperosmotic environment affects intracellular transport and energy generation in renal tubular epithelial cells, leading to vacuolization and even necrosis. (2) Renal microvascular hemodynamic changes: The contrast agent can increase and then continuously decrease the blood flow of the renal artery. The reasons may be as follows: (a) The contrast agent increases the pressure in the renal tubules, leading to a decrease in renal blood flow; (b) the contrast agent has a direct contractile effect on smooth muscle cells; (c) increased renal tubular osmotic pressure leads to increased tubular ball feedback; and (d) contrast agent-mediated release of endogenous vasoconstrictor factors, such as adenosine. (3) Renal reperfusion and oxygen free radical damage: Renal reperfusion leads to the release of oxygen free radicals, causing kidney damage, decreases antioxidant capacity storage in patients with chronic renal insufficiency and diabetes, and increases baseline oxidative stress response, making them more prone to CIN. (4) Inflammatory response: Compared with other tissues, the renal parenchyma is more easily damaged by contrast agent-mediated complement and inflammatory cytokines in the body. (5) Renal tubule blockage: Protein deposition in the renal tubules caused by contrast agents is considered likely to lead to CIN.

At present, the prevention and treatment of CIN includes standard hydration; this is the only clinically accepted method for the prevention and treatment of CIN, but it has many limitations (such as the possibility of aggravating cardiac insufficiency and long application time). Alprostadil is a kind of targeted therapeutic effect of prostaglandin E1 preparation. Alprostadil has extensive physiological and pharmacological effects, which can dilate blood vessels, inhibit platelet aggregation, inhibit histamine release, eliminate circulating immune complexes, and discharge sodium and diuretic.^31–35 Alprostadil can directly dilate the renal artery, increase renal blood flow and GFR, and inhibit sodium reabsorption by the renal tubules, with a good protective effect on renal function. Most of the adverse reactions are related to the vasodilatory effect of the drug, resulting in headache, redness, and swelling at the injection site, which disappear after infusion. In CIN, alprostadil can be targeted to accumulate in the lesion site, selective renal vascular expansion, increase renal blood flow, and can inhibit platelet aggregation, prevent thrombosis and the stability of cell membrane lysosome membrane, prevent reperfusion tissue damage, can change the red blood cell deformation ability, and make it easy to through the capillaries and improving microcirculation.^36,37

In a similar meta-analysis, Xie et al³⁷ found that the incidence of CIN in the experimental (alprostadil plus hydration) group was significantly lower than that in the control (hydration) group. The level of Scr, CysC, BUN, and β2-microglobulin in the experimental group was lower than that in the control group. Creatinine clearance rate and estimated GFR in the experimental group were higher than those in the control group. In our study, we made the meta-analysis based on the dose of alprostadil: 10, 20, and 40 µg/d and others (10/20/40 ng/kg/min for 6 hours).

In this meta-analysis, compared with hydration, 10 µg/d alprostadil plus hydration significantly decreased the incidence of CIN (RR: 0.391, 95% CI, 0.285-0.536), decreased Scr at 48 hours and 7 days, decreased NGAL at 24 and 48 hours, and increased GFR at 24 and 72 hours. Compared with hydration, 20 µg/d alprostadil plus hydration significantly decreased the incidence of CIN (RR: 0.405, 95% CI, 0.317-0.518) and AEs (RR: 0.502, 95% CI, 0.307-0.820); decreased Scr at 48 and 72 hours and 7 days; decreased CysC at 24, 48, and 72 hours; reduced NGAL at 24, 48, and 72 hours; increased GFR at 24 hours; decreased BUN at 48 and 72 hours and 7 days; and reduced MG at 48 and 72 hours. There has no significant difference in the incidence of CIN (RR: 1.647, 95% CI, 0.425-6.388) and AEs (RR: 0.142, 95% CI, 0.018-1.135) between patients receiving 40 µg/d alprostadil plus hydration and patients receiving hydration. Furthermore, 40 µg/d alprostadil plus hydration significantly decreased Scr at 7 days versus hydration.

Sensitivity analysis showed that no studies had a significant effect on the results. The funnel plot, Begg and Mazumdar rank test, and Egger test showed no significant bias risk in the included studies. Therefore, the results of the meta-analysis are reliable. However, the present meta-analysis has some limitations: We only included English and Chinese studies, our analysis was based on secondary data, and the original data were not available.

In conclusion, 10 µg/d alprostadil plus hydration significantly decreased the incidence of CIN, decreased Scr and NGAL, and increased GFR (Ps < .05). Furthermore, 20 µg/d alprostadil plus hydration significantly decreased the incidence of CIN and AEs; decreased Scr, CysC, NGAL, BUN, and MG; and increased GFR (Ps < .05). Additionally, 40 µg/d alprostadil plus hydration significantly decreased Scr (P < .05).

Footnotes

Authors’ Note

HX and HW have made substantial contributions to conception and design of the study and wrote the manuscript; CZ, JX, and NH searched literature; XT, ZZ, and JX reviewed all literature; CZ, JX, and NH extracted data from the collected literature and analyzed the data; and HX revised the manuscript. All authors approved the final version of the manuscript.

All data generated or analyzed during this study are included in this published article.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Jun Xiao, MM

References

Owen

Hiremath

Myers

Fraser-Hill

Barrett

. Canadian Association of Radiologists consensus guidelines for the prevention of contrast-induced nephropathy: update 2012. Can Assoc Radiol J. 2014; 65:96–105.

Grossman

Ali

Aronow

, et al. Contrast-induced nephropathy in patients undergoing endovascular peripheral vascular intervention: Incidence, risk factors, and outcomes as observed in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium. J Interv Cardiol. 2017; 30:274–80.

Uzunhasan

Yildiz

Arslan

, et al. Contrast-Induced Acute Kidney Injury Is Associated With Long-Term Adverse Events in Patients With Acute Coronary syndrome. Angiology. 2017; 68:621–6.

Heyman

Rosen

Khamaisi

Idée

Rosenberger

. Reactive oxygen species and the pathogenesis of radiocontrast-induced nephropathy. Invest Radiol. 2010; 45:188–95.

Pisani

Riccio

Andreucci

, et al. Role of reactive oxygen species in pathogenesis of radiocontrast-induced nephropathy. Biomed Res Int. 2013; 2013:868321.

Guan

Chen

Zuo

, et al. Contrast Media-Induced Renal Inflammation Is Mediated Through HMGB1 and Its Receptors in Human Tubular Cells. DNA Cell Biol. 2017; 36:67–76.

Guyatt

Oxman

Akl

, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011; 64:383–94.

Liu

Zhang

Guo

Wei

. Renoprotective effect of alprostadil in combination with statins in patients with mild to moderate renal failure undergoing coronary angiography. Chin Med J. 2013; 126:3475–80.

Qian

, et al. Prevention of contrast-induced nephropathy with prostaglandin E1 in high-risk patients undergoing percutaneous coronary intervention. Int Urol Nephrol. 2014; 46:781–6.

10.

Liang

Yang

. Efficacy of alprostadil in preventing contrast-induced nephropathy in patients undergoing percutaneous coronary intervention: A multicenter prospective randomized controlled trial. 2018; 91:742–50.

11.

Miao

Zhong

Yan

Wang

Jin

. Alprostadil plays a protective role in contrast-induced nephropathy in the elderly. Int Urol Nephrol. 2013; 45:1179–85.

12.

Wang

, et al. Alprostadil protects type 2 diabetes mellitus patients treated with metformin from contrast-induced nephropathy. Int Urol Nephrol. 2017; 49:2019–26.

13.

Cai

Chen

Zhu

Wang

. Combined use of hydration and alprostadil for preventing contrast-induced nephropathy following percutaneous coronary intervention in elderly patients. Exp Ther Med. 2013; 6:863–7.

14.

Yang

Zhang

, et al. Preventive Effects of Alprostadil Against Contrast-Induced Nephropathy Inpatients With Renal Insufficiency Undergoing Percutaneous Coronary Intervention. Angiology. 2018; 69:393–9.

15.

Koch

Plum

Grabensee

Mödder

. Prostaglandin E1: a new agent for the prevention of renal dysfunction in high risk patients caused by radiocontrast media? PGE1 Study Group. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 2000; 15:43–9.

16.

Dai

Wang

Han

Wang

. Preventive effect of alprostadil on contrast-medium nephropathy in patients undergoing coronary intervention. Shandong Medical Journal. 2012; 52:62–3.

17.

Wang

Liu

. Effect of Alprostadil on Contrast Nephropathy in Patients with Coronary Heart Disease and Diabetes after Intervention. China Practical Medicine. 2016; 11:174–5.

18.

Wang

Peng

Gong

Cai

Liu

. Effect of Alprostadil on Contrast Nephropathy in Patients with Coronary Heart Disease and Diabetes after Interventional Therapy. Journal of Southeast China National Defence Medical Science. 2014; 16:28–30.

19.

Zhou

. Preventive effect of alprostadil on contrast-induced nephropathy in patients undergoing coronary intervention. Chinese Journal of Postgraduates of Medicine. 2013; 36:34–6.

20.

Cui

Jiang

Huang

Lao

. The effects of alprostadil on oxidative stress in acute myocardial infarction patient treated by emergency percutaneous coronary intervention. Guangdong Medical Journal. 2012; 33:1172–4.

21.

Chen

. Preventive effect of alprostadil on contrast-medium nephropathy in interventional therapy of coronary heart disease patients with diabetes. Diabetes New World. 2017:71–2.

22.

Liu

Zhang

. Clinical observation on the protective effect of alprostadil on renal injury after interventional operation. The Journal of Practical Medicine. 2012; 28:2952–3.

23.

Wang

. Preventive effect of alprostadil on contrast-medium nephropathy in elderly patients with coronary heart disease after interventional therapy. Chinese Journal of Primary Medicine and Pharmacy. 2018; 25:1816–9.

24.

Yang

Zhang

, et al. Preventive effect of alprostadil for contrast-induced nephropathy in elderly CHD patients. Chinese Journal of Geriatric Heart Brain and Vessel Diseases. 2019; 21:366–70.

25.

Zhang

. Research of prostaglandin E1 and vitamin C in the prevention of contrast induced nephropathy. Chinese Journal of Practical Medicine. 2016; 43:9–11.

26.

Ban

Shi

Zhou

, et al. The effect of alprostadil combined with hydration treatment on contrast-medium nephropathy after coronary stent surgery. Anhui Medical and Pharmaceutical Journal. 2015;19:1000 -1.

27.

Zhang

, et al. Preventive effect of combined application of alprostadil and reduced glutathione on contrast-medium nephropathy after PCI in patients with coronary heart disease. Shandong Medical Journal. 2015; 55:49–50.

28.

Huang

SHen

. The preventive effect of alprostadil lipo preparation on contrast induced nephropathy in patients with PCI. Chinese Journal of Difficult and Complicated Cases. 2016; 15:154–7.

29.

Yang

Han

Liu

. Clinical evaluation of Lipo-PGEl on prophylaxis of radiocontrast-induced nephropathy in elder patients. Chinese Journal of New Drugs. 2006; 15:1386–8.

30.

Xia

Jin

Shen

Mao

. Effect of Alprostadil Injection on Contrast Nephropathy in Patients with Cardiac Insufficiency After Coronary Intervention. J Clin Med. 2012; 29:1128–30.

31.

Zheng

Huang

Luo

Shen

. Preventive effect of alprostadil injection on contrast-medium nephropathy. Zhejiang Journal of Integrated Traditional Chinese and Western Medicine. 2015; 25:772–3.

32.

Yang

. Role of prostaglandin E1 in preventing contrast-induced nephropathy in elderly CHD patients after PCI. Chinese Journal of Geriatric Heart Brain and Vessel Diseases. 2019; 21:245–9.

33.

Cai

CHen

Zhu

, et al. Preventive effect of hydration combined with alprostadil on contrast-induced nephropathy in elderly patients with coronary heart disease after coronary intervention. Guangdong Medical Journal. 2012; 33:2799–801.

34.

Wang

Zheng

Yang

Cai

. Preventive effect of hydration combined with alprostadil on contrast-medium nephropathy in elderly diabetic patients undergoing coronary intervention. Chongqing Medicine. 2019; 48:3924–6.

35.

Cai

. Efficacy of Hydration and Alprostadil PreVention of Coronary Heart Disease in Elderly Patients with Coronary Angiography after Contrast-induced Nephropathy(CAN). Modern Diagnosis and Treatment. 2014; 25:5052–3.

36.

Liu

Long

. Effects of Lipo-PGE1 on Prophylaxis of Radiocontrast-induced Nephropathy and Hemorrheology in Patients with Coronary Heart Disease. Chinese Journal of Hemorheology. 2011; 21:597–602.

37.

Xie

Jiang

Lin

Deng

Effect of Alprostadil on the Prevention of Contrast-Induced Nephropathy: A Meta-Analysis of 36 Randomized Controlled Trials. Angiology. 2019; 70:594–612.