Acta Medica Mediterranea, 2020, 36: 1369

CLINICAL STUDY OF PITAVASTATIN COMBINED WITH ACETYLCYSTEINE IN THE PREVENTION OF CONTRAST-INDUCED NEPHROPATHY IN PATIENTS

Yugang Zu1, #, Xiaoqiong Zhang2, #, Shujun Zhao1, * 1Department of Internal Medicine-Cardiovascular, The Affiliated Hospital of Hebei University, Baoding, PR China - 2Department of Internal Medicine-Cardiovascular, Baoding Second Hospital, Baoding, PR China #These authors contributed equally to this work as co-first author

ABSTRACT

Objective: To analyze the clinical efficacy of pitavastatin combined with acetylcysteine in the prevention of contrast-induced nephropathy (CIN). Methods: Patients with diabetic nephropathy who received coronary intervention with Ultravist 370 in the De- partment of Cardiology from May 2018 to May 2019 were selected for a study involving 80 patients. The patients were divided into treatment groups according to a random number table: one group received pitavastatin, the acetylcysteine group was adminis- tered with acetylcysteine, the control group received no further treatment, and the combination group received pitavastatin combined with acetylcysteine. There were 20 cases in each group. Changes in serum creatinine (Scr), β2-microglobulin (β2-MG), urea nitrogen (BUN), 24 h total urinary microprotein (24hUpro), and urinary albumin excretion rate (UARE) levels were observed in all patients 2 d before and 3 d, and 7 d after PCI to calculate the random urinary albumin/creatinine ratio (ACR). The occurrence of CIN after percutaneous coronary intervention (PCI) was recorded. Results: After surgery, the levels of 3 d Scr, β2-MG, BUN, 24hUpro, UARE, and ACR in the four groups were higher than those before surgery. The levels of Scr, β2-MG, BUN, 24hUpro, UARE and ACR in the control group were significantly higher than those in the statin group, acetylcysteine group and combination group (P<0.05). Scr, β2-MG, BUN, 24hUpro, UARE, and ACR levels in the combination group were significantly lower than the statin group and acetylcysteine group (P<0.05); The levels of Scr, β2-MG, BUN, 24hUpro, UARE and ACR in the combination group were significantly lower than those in the other three groups (P<0.05). The incidence of CIN in the combination group was 5%, which was significantly lower than the other three groups, and the difference was statistically significant (P<0.05). Conclusion: Pitavastatin combined with acetylcysteine can significantly reduce renal function dam- age caused by PCI, improve oxidative stress and reduce the incidence of CIN.

Keywords: Pitavastatin, acetylcysteine, contrast-induced nephropathy, clinical efficacy.

DOI: 10.19193/0393-6384_2020_3_212

Received November 30, 2019; Accepted January 20, 2020

Introduction rapid development of interventional techniques for cardiovascular disease, more and more patients with Contrast-induced nephropathy (CIN) is the re- cardiovascular disease undergo percutaneous coro- nal damage occurring within 36~72 h after applica - nary intervention (PCI), and CIN has become one tion of contrast-enhanced agents, and the diagnostic of the common complications after PCI. However, criteria are serum creatinine (Scr) absolute value its pathogenesis is quite complicated and unclear. increased by > 0.5 mg/L (44.2 µmol/L), or 25% Relevant data(2) show that oxidative stress and renal higher than before contrast (1). Clinical symptoms of medullary ischemia are the main pathogenesis of CIN patients are atypical, usually characterized by CIN. Effective preventive measures before PCI can non-oliguric renal function damage. Urine examina- significantly reduce the risk of morbidity. tion may indicate acute tubular necrosis, but glomer- Pitavastatin is a primary and secondary pre- ular lesions are not obvious. In recent years, with the ventive for clinical hypertension and cardio - 1370 Yugang Zu, Xiaoqiong Zhang et Al vascular and cerebrovascular diseases. It belongs Treatment methods to hydroxymethylglutaryl coenzyme A reductase Patients in the four groups were given a slow inhibitor class of , which has anti-atheroscle - intravenous infusion of 0.9% sodium chloride 500 rosis, anti-inflammatory and anti-oxidation proper - mL at 12 h before surgery for hydration treatment, ties and promotes angiogenesis. Its pharmacokinetic which lasted 24 h after surgery. In the statin group, 4 properties are excellent, and bioavailability is high(3). mg pitavastatin was given orally on day 1 before sur- Acetylcysteine is a sulfur-containing antioxidant gery (specification: 2 mg/tablet, produced by China that inhibits the production of angiotensin-convert - Resources Double-crane Pharmaceutical Co., Ltd., ing enzymes through its anti-oxidation, anti-toxic - batch number: 160830), and 4 mg pitavastatin was ity, and anti-free radical activity and regulation of given orally on day 3 after PCI. Acetylcysteine ef- cellular , thereby reducing the damage fervescent tablets 1200 mg (specification: 600 mg/ of the contrast agent on renal function (4). Therefore, tablet, Zhejiang Jinhua Conba Pharmaceutical Co., this study aimed to analyze the clinical efficacy of Ltd., batch number: 150420) were taken twice a day pitavastatin combined with acetylcysteine in the pre- in the acetylcysteine group, and the same dose was vention of contrast-induced nephropathy. taken orally for 3 days after PCI. In the combina - tion group, pitavastatin and acetylcysteine were used Data and methods together at the same dosage as above. The control group received no further treatment. All patients Object sources in the four groups were treated with iodohydrin, a Patients with diabetic nephropathy who re- low-osmotic non-ionic contrast agent (trade name: ceived coronary intervention with Ultravist 370 con- osu, at a concentration of about 800 mOsm/kg, pro- trast agent in the Department of Cardiology from duced by the Yangtze River Pharmaceutical Group). May 2018 to May 2019 were selected for a study of Before the intervention, non-steroidal anti-inflam - 80 patients. This study was approved by the hospital matory drugs, metformin, aminoglycoside and other ethics committee. nephrotoxic drugs should be discontinued, while hy- Inclusion criteria: poglycemic agents, low-molecular weight heparin, • All patients met the diagnostic criteria of CIN anti- agents, β-receptor-blocking agents and established by the European Society of Urogenital so on should be routinely applied. (5); • No contrast agent was used 1 week before PCI; Detection method • Complete clinical case data; Fasting venous (2 mL) from all patients • Patients and their families informed and was collected 2 d before PCI, 3 d after PCI, and 7 d signed the consent form. after PCI. The blood was centrifuged by centrifugal Exclusion criteria: force at 3000r/min for 10 min, and then the super- • Severe liver and kidney dysfunction; charger EP tube was taken and placed in a refrigera- • Allergic to contrast agent and cannot tor at -80 °C for later use. All the patients collected tolerate; 3 mL of any midstream urine 2 d before PCI and 3 d • Patients who received , NSAIDs or ace- and 7 d after PCI. After centrifugation, the superna- tylcysteine 2 weeks before PCI; tant was taken and placed in a refrigerator at -80 °C • Patients receiving renal dialysis before surgery; for later use. The changes of Scr, β2-microglobulin • Emergency PCI patients with acute myocar - (β2-MG), blood urea nitrogen (BUN), 24-hour uri- dial infarction; nary protein (24hUpro), and urinary albumin excre- • Co-, trauma, malignant tumour. tion rate (UARE) level were detected by automatic Among the 80 patients, 48 were male, and 32 biochemical analyzer to calculate the random uri- were female, aged 37-79 years old, with an average nary albumin/creatinine ratio (ACR). age of 62.60±10.31 years old. All patients were randomly divided into the Statistical methods statin group (20 cases), the acetylcysteine group (20 In this study, all measurement data were rep- cases), the control group (20 cases), and the combi- resented by (x̅±s), the comparison of data between nation group (20 cases). After statistical examina- each group was conducted by variance analysis and tion, the general data of the four groups were com- the comparison of data between the two groups parable (P>0.05). by independent sample least significant difference Clinical study of pitavastatin combined with acetylcysteine in the prevention of contrast-induced nephropathy in... 1371

(LSD) t-test. All the count data were expressed by UARE (mg/24 h) 24hUpro (mg/d)

[n (%)], and the data of each group were compared Group Cases 2 preoperative postoperation postoperation preoperative postoperation postoperation by χ test. P<0.05 was considered statistically sig- 2d 3d 7d 2d 3d 7d nificant. The data of this study were analyzed by the SPSS v. 13.0 software package. Statin 20 52.87±10.23 60.46±11.78abc 58.65±9.13ac 15.86±2.11 20.63±2.90abc 19.82±2.63ac

abc ac abc ac Results Acetylcysteine 20 53.49±9.87 60.80±10.17 58.49±9.38 15.75±2.17 21.14±3.01 19.14±2.53

Control 20 52.39±10.12 67.61±11.75a 60.49±9.16ac 15.81±1.98 28.20±3.42a 25.86±3.08ac Comparison of Scr and BUN levels before and after PCI in each group Combination 20 52.68±10.36 54.23±10.02b 51.72±9.86 15.92±2.03 16.16±2.83b 14.39±2.74 Three days after surgery, the Scr and BUN levels of the four groups of patients were all high- Table 2: Comparison of UARE and 24hUpro levels befo- re and after PCI in each group (x̅±s). er than those before surgery. Scr and BUN levels a Note: Compared with preoperative 2d P<0.05; Compared with in the control group were significantly higher than the control group at the same time bP<0.05; Compared with the those in the statin group, acetylcysteine group and combination group cP<0.05. combination group (P<0.05). Scr and BUN levels in the combination group were significantly low- Comparison of β2-MG and ACR levels er than those in the statin group and acetylcysteine before and after PCI in each group group (P<0.05). Seven days after surgery, the Scr Three days after the operation, the levels of β2- and BUN levels in the combined group were sig- MG and ACR in the four groups were higher than nificantly lower than those in the other three groups those before surgery. The levels of β2-MG and ACR (P<0.05). See Table 1. in the control group were significantly higher than those in the statin group, acetylcysteine group and Scr (µmol/L) BUN (mmol/L) combination group (P<0.05). The levels of β2-MG Group Cases preoperative postoperation postoperation preoperative postoperation postoperation and ACR in the combination group were significant- 2d 3d 7d 2d 3d 7d ly lower than those in the statin group and acetyl -

Statin 20 81.56±10.07 99.10±12.15abc 87.04±5.40ac 16.53±4.27 20.64±4.27abc 19.30±3.24ac cysteine group (P<0.05). Seven days after the opera- tion, the β2-MG and ACR in the combination group Acetylcysteine 20 82.67±9.32 107.22±12.41abc 88.12±7.36ac 16.34±4.30 20.13±4.38abc 19.23±3.17ac were significantly lower than those in the other three groups (P<0.05). See Table 3. Control 20 81.82±11.51 115.84±13.07a 94.63±6.45ac 17.08±4.49 25.54±4.23a 19.80±3.39ac

β2-MG (mg/L) ACR (3 mg/mmol)

b b Combination 20 82.22±9.65 87.24±10.64 83.04±6.16 16.61±4.32 17.53±3.26 15.81±2.86 Group Cases preoperative postoperation postoperation preoperative postoperation postoperation 2d 3d 7d 2d 3d 7d Table 1: Comparison of Scr and BUN levels before and after PCI in each group (x̅±s). Statin 20 23.69±3.14 26.98±4.03abc 26.77±3.20ac 5.32±1.67 13.64±3.26abc 11.47±2.36ac Note: Compared with preoperative 2d aP<0.05; Compared with b the control group at the same time P<0.05; Compared with the Acetylcysteine 20 22.63±4.04 27.02±4.18abc 26.98±4.16ac 5.15±1.33 13.26±3.28abc 11.82±2.47ac combination group cP<0.05.

Control 20 22.66±3.98 32.26±3.15a 27.92±4.01ac 5.42±1.43 16.57±3.58a 13.52±2.27ac Comparison of UARE and 24hUpro levels before and after PCI in each group Combination 20 23.03±4.01 26.77±3.25ab 22.98±3.77 5.48±1.32 6.15±1.74b 4.03±1.20 Three days after surgery, UARE and 24hUpro Table 3: Comparison of β2-MG and ACR levels before levels in all four groups were higher than those be- and after PCI in each group (x̅±s). fore surgery. The levels of UARE and 24hUpro in Note: Compared with preoperative 2d aP<0.05; Compared with the control group were significantly higher than the control group at the same time bP<0.05; Compared with the those in the statin group, acetylcysteine group and combination group cP<0.05. combination group (P<0.05). The level of UARE and 24hUpro in the combination group was signif- Comparison of CIN occurrence after PCI in icantly lower than that of the statin group and the each group acetylcysteine group (P<0.05). Seven days after sur- The incidence of CIN in the combination group gery, the UARE and 24hUpro in the combination was 5%, which is significantly lower than the other group were significantly lower than those in the oth- three groups, and the difference was statistically sig- er three groups (P<0.05). See Table 2. nificant (P<0.05). 1372 Yugang Zu, Xiaoqiong Zhang et Al

Group Cases CIN occurrence tion in clinical practice. It can break the disulfide

Statin 20 3 (15%) bond of mucin in sputum and reduce the viscosity of sputum(10). In addition, it is an antioxidant and Acetylcysteine 20 5 (25%) superoxide dismutase scavenger that can directly Control 20 8 (40%) scavenge oxygen free radicals, maintain calcium Combination 20 1 (5%) balance, promote the release of vasodilators such as χ² 7.993 nitric oxide, reduce proteinuria and improve local P 0.046 kidney microcirculation. Acetylcysteine can prevent Table 4: Comparison of CIN occurrence after PCI in each apoptosis caused by reactive oxygen species in is- (11) group. chemia-reperfusion cells . In order to enhance the intervention of antioxidants, it can work synergisti- Discussion cally in combination with other drugs. Pitavastatin is a first-line drug for high cholesterol treatment, With the wide application of iodine contrast with anti-atherosclerosis, anti-oxidative stress, vas- agents in the diagnosis and treatment of imaging and cular endothelium production, immune regulation, interventional radiology, the number of patients re- anti-inflammation and a variety of additional phar - ceiving treatment has increased dramatically. Cardi- macological effects(12). In addition, it can also protect ovascular patients benefit from contrast imaging, but the kidney by inhibiting tubulointerstitial damage at the same time, the kidney function damage caused and regulating glomerular blood flow. Pitavastatin is by iodine contrast agent gradually becomes one of highly selective for the liver, has a long half-life, few the serious diseases that endanger human health. drug interactions, and fewer adverse effects(13). CIN has a complex pathogenesis, which is currently At present, the diagnosis of renal injury mainly considered to be closely related to oxidative stress relies on related renal function indicators. Scr and injury, renal medulla ischemia and hypoxia, and con- BUN are commonly used as indicators of renal func- trast agent toxicity (6). The pathological mechanism tion. The increase in the level of these values often of renal injury caused by the contrast agent has not indicates that the damage is serious (14). The increase been clearly studied. Relevant data show that a con- of β2-MG level can effectively reflect the glomerular trast agent can directly act on renal tubules, inhibit filtration function; 24hUpro and UARE are impor - the activity of antioxidant enzymes by reducing the tant indicators for evaluating the therapeutic effect level of adenine nucleic acid and the concentration of nephropathy and help to judge the prognosis of of potassium ions in cells, release a large number of patients; ACR detection is currently a clinically rec- oxygen free radicals, and cause lipid peroxidation(7). ognized effective screening method for early diabetic At the same time, the contrast agent can combine nephropathy(15). The results of this study showed that with the Tamm-Horsfall protein in renal tubules to the combination of pitavastatin and acetylcysteine form protein tubules, causing renal cell apoptosis compared with the two drugs alone can significantly and protein obstruction of renal tubules. In addition, reduce the above-mentioned indicators and reduce after using a contrast agent, the body can release a the incidence of CIN. In summary, pitavastatin com- large amount of oxides, causing contraction of vas- bined with acetylcysteine treatment can significantly cular smooth muscle, leading to renal ischemia and reduce renal function damage caused by PCI sur - hypoxia, and causing renal inflammation, tubular gery, improve oxidative stress response, and reduce necrosis and other ischemic changes(8). Some schol- the incidence of CIN. ars have found that contrast agents can reduce the activity of superoxide dismutase and catalase in the kidney and enhance the lipid peroxidation of the re- References nal cortex. The cytotoxic effect of oxygen free rad- (9). icals can directly damage the renal tubular cells 1) Barbieri L, Verdoia M, Suryapranata H, De Luca G. Im- At present, clinical prevention of CIN is most- pact of vascular access on the development of contrast ly based on hydration therapy. It is very important induced nephropathy in patients undergoing coronary to take appropriate drug-assisted hydration therapy and/or percutaneous coronary intervention. for prevention of renal damage. An antioxidant is a Int J Cardiol 2019; 275: 48-52. 2) Rear R, Bell RM, Hausenloy DJ. Contrast-induced ne- commonly used preventive drug. Acetylcysteine is phropathy following angiography and cardiac interven - used as an expectorant for respiratory tract infec- tions. Heart 2016; 102: 638-648. Clinical study of pitavastatin combined with acetylcysteine in the prevention of contrast-induced nephropathy in... 1373

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