Advancements in percutaneous coronary intervention (PCI)-related technology have led to increased procedures annually and the enhanced use of contrast media (CM) (1). CIN is a severe complication of invasive cardiovascular procedures performed using CM (2). During angiographic or other medical procedures, CIN is a reversible acute renal failure observed after administering iodinated CM. It is the increase in serum creatinine (Scr) levels of ≥25% or an absolute increase of ≥0.5 mg/dl (44.2 mmol/L) from baseline value after 48–72 h of CM exposure (3, 4). The exact mechanism involved in CIN is unclear. However, it could be associated with hemodynamic effects, renal tubular cytotoxicity, renal medullary ischemia, hypoxia, and the inflammatory response and oxidative stress injury mediated thereby (5–8). CIN incidence in patients with normal renal function is not high. In contrast, factors such as advanced age, diabetes, and high-dose CM could elevate CIN incidence.

CDDP is a pure Traditional Chinese medicine developed using modern high-tech means, which has been used for 20 years to treat coronary heart disease (9). Its main components include Salvia miltiorrhiza, Panax notoginseng, and Dipterocarpaceae (10). Modern pharmacological studies revealed that CDDP has antioxidant and anti-inflammatory properties. They also protect endothelial function, inhibit platelet adhesion, increase coronary vascularity, and improve microcirculation (11). Recently, CDDP has been frequently used to treat CHD sufferers combined with PCI. Previous studies have established that CDDP pre-treatment can decrease CIN occurrence in PCI patients, indicating that early use of CDDP before PCI is appropriate adjuvant drug therapy. However, the mechanism of action on CDDP to prevent CIN remains unclear (12). CDDP mechanism was further analyzed to avoid CIN by detecting inflammatory indicators of apoptosis and oxidative stress indicators before and after PCI.

Based on admission electrocardiogram (ECG) and preliminary laboratory results, 989 patients were identified as study candidates. Eligible patients who agreed to enter the study were sequentially assigned to two groups (1:1) based on computer-generated random numbers. All patients received loading doses of aspirin and clopidogrel (300 mg each) before CAG/PCI. Clinicians can decide whether to use the following medicines based on clinical requirements or guidelines, including β-antagonist, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), diuretics, and a statin. Patients who underwent only CAG were excluded (mild coronary artery stenosis or severe coronary artery lesions require CABG). Patients were given the same instructions for procedure preparation and post-procedure recovery.

Patients allocated to the hydration group received only received hydration therapy (0.9% sodium chloride), because related studies have proved that hydration in the perioperative period is effective in preventing the occurrence of CIN (14). Prophylactic hydration protocols used were according to current guidelines: intravenous 0·9% NaCl 1 ml/kg per h during 12 h before and 12 h after contrast administration (at least 1,000 ml). Hydration rate was reduced to 0.5 ml/kg/h for patients with LVEF ≤45%. Patients in the CDDP group took compound Danshen Dripping Pills (Tianjin Tasly Pharmaceutical Group Co., Ltd., specification: 27 mg/capsule) orally 2 days before surgery at the same time as the hydration therapy, 10 capsules/time, 3 times/day; continuous oral administration after surgery, 10 capsules/time, 3 times/day, for 14 day. Iodoprolamide (Bayer medical and health care Co., Ltd, Leverkusen, Germany) contrast agent was used in all patients during PCI.

Of the 1,190 patients initially enrolled in the study, 47 were treated with CM 14 days before PCI, 10 were treated with nephrotoxic drugs, 26 had severe renal and cardiac dysfunction, 2 had STEMI after admission, 4 had suspected malignancies, 95 were enrolled in another randomized trial, and 17 were admitted to an isolation unit. 989 patients were randomly divided into hydration group and CDDP group. CAG test alone was excluded, and patients with postoperative delirium, CM allergy and severe data loss were excluded. A total of 822 patients were included for statistical analysis and 751 were followed up (Figure 1). A total of 29 cases of MACE occurred in both groups during 30 days of follow-up (Hydration group: 15 cases of unstable angina pectoris, 1 case of acute heart failure; CDDP group: 1 case of cerebrovascular event, 12 cases of unstable angina pectoris) The incidence of MACE in 751 follow-up patients showed no significant difference between the two groups.

This study evaluated the association between perioperative CDDP use and CIN incidence in patients with non-ST-segment elevation acute coronary syndromes demanding interventional treatment with contrast agents. This prospective, randomized, controlled trial revealed that CDDP combined with hydration therapy significantly decreased the risk of CIN through anti-inflammatory and antioxidant stress effects. Moreover, LVEF < 50%, CM ≥ 160 ml, and hypertension are CIN high-risk factors in patients.

Procedures with intravascular iodinated contrast material pose a risk to renal function, especially in patients with compromised renal functions. CIN is a frequent complication after intravascular CM administration. It is the third most common cause of acute kidney injury among hospitalized patients, second only to ischemic and drug-induced injuries (4). Patients with CIN have a greater risk for non-renal complications, such as cardiac, vascular, and systemic problems. Treatment is limited to supportive measures in patients who develop CIN until renal impairment resolves (15). Many studies have shown that inflammation and oxidative stress are necessary for renal dysfunction and deterioration. CIN can be regarded as renal impairment due to CM, which stimulates the response of pro-inflammatory factors, including tumor necrosis factor, interleukin-6, and IL-1 family cytokines in vivo. This directly leads to renal tubular epithelial cell damage and an elevated risk of CIN (16, 17). CM with high viscosity characteristics can lead to toxicity to renal tubule cells. Moreover, CM affects the blood oxygen delivery by renal tubule cells, triggers the release of reactive oxygen species, and elevates oxidative stress and free radical formation. This damages the cell membrane and nucleic acid and consumes NO, leading to enhanced oxygen consumption (18).

CDDP is a pure Chinese medicine drop with high efficiency, quick effect, and multi-effect developed by modern pharmaceutical technology. The main chemical components have three traditional Chinese medicines (19): Salvia miltiorrhiza, pseudo-ginseng, and borneol. Salvia miltiorrhiza has water-soluble tanshinol, salvianolic acid B, and protocatechualdehyde as active ingredients. Water-soluble tanshinol can reduce platelet aggregation and possesses various pharmacological effects. These include anticoagulation, lipid regulation, calcium ion antagonism, fibroblast proliferation and matrix secretion inhibition, and anti-inflammatory effects by inhibiting cell surface adhesion molecules. Total saponins are the active ingredients of Panax notoginseng extracted from Panax notoginseng. Borneol is made of borneol gum with main functions such as heat-clearing, deswelling, and detumescence. Modern pharmacological studies indicate that borneol has anti-inflammatory and antibacterial effects (20–23). Moreover, the potential mechanism of CDDP on myocardial ischemia involves energy metabolism regulation. This includes regulating the primary energy production mode of ischemic heart tissue, thereby inducing metabolic transformation to fatty acid metabolism (24).

ACS patients suffer from excessive inflammation and endothelial dysfunction, ongoing platelet aggregation, cell adhesion, and microcirculation obstruction after PCI. NGAL and TNFα are highly sensitive inflammatory markers, indicating the inflammatory state of the body. NGAL is a relatively small protein of the lipocalcin family that is the response of the nephron to tubular epithelial damage (25). Recent evidence indicates that NGAL levels are enhanced and stable in acute kidney injury, readily detectable in serum (26, 27). Thus, elevated NGAL levels could predict CKD progression and serve as an early kidney damage marker (28). NFα is mainly composed of monocytes and macrophages. TNF-α inhibits the expression of endothelial nitric oxide synthase (eNOS) in endothelial and vascular smooth muscle cells. This increases the NF-κB pathway activation through eNOS mRNA instability and NADPH oxidase activation to induce inflammation (29–31). Reactive oxygen species are products of aerobic metabolism and are involved in different pathological states of acute kidney injury (AKI) along with mitochondrial oxidative stress and autophagy. Enzyme and non-enzyme defense systems in mitochondria eliminate excess ROS to protect cells from oxidative stress (32). SOD and others constitute the scour enzyme system regulating mitochondrial ROS. Thus, SOD converts superoxide anions (the most dangerous ROS produced) into hydrogen peroxide and eventually into H₂O (33, 34). Therefore, the serum levels of NGAL and TNFα significantly differed between the two groups at 48 h after applying CM. NGAL levels were higher in the hydration group than those in the CDDP group at 48 h and 72 h, indicating different degrees of inflammatory damage to kidney function. SOD and MDA contents were higher in the hydration group than those in the CDDP group at 48 h and 72 h, depicting that oxidative stress was involved in affecting renal function. Bax, Bcl-2, and Caspase-9 decreased at 48 h and 72 h in the CDDP group with a changing trend but no statistical significance (P > 0.05).

At present, many animal experiments have been conducted to explore the pathogenesis of CIN. Some studies have found that NGAL levels in CIN rat models exposed to dehydration and CM are significantly increased, and the renal tubule ultrastructure changes are serious, which are represented by mitochondrial swelling, mitochondrial membrane rupture, and ridge disappearance (35). By reducing rat food intake by 40% 4 weeks prior to CM injection, it was found that caloric restriction (CR) reduced CM-induced apoptosis, ROS, and inflammation in rat extrinsic medulli via the SIRT1/GPX4 pathway (36). In addition, the degree of oxidative stress was different in different anatomical renal areas. Evaluation of blood flow and histopathology in different anatomical renal areas (medullary, cortical, and perimedullary) in New Zealand rabbits showed that renal toxicity was clearly confined to the cortex and extramedullary, with characteristic tubular necrosis and vacuolation. The medullary areas appear to be more widely but less severely affected, and the REDOX status of the cortical areas is severely affected (37). Cytological observation of touch preparation technique (TPT) also showed that CM-induced ROS production, apoptosis and cell degeneration led to renal cytopathosis (38). Studies have found that the kidney protection effect of some commonly used clinical drugs is mainly through the antioxidant effect to prevent kidney toxicity (39, 40). These results are similar to those of our previous animal studies (7, 8).

The risk factors for coronary heart disease still exist after PCI. When the infarct vessel recanalization, it will also cause certain damage to the vascular endothelium, resulting in the recurrence of angina pectoris, arrhythmia, heart failure and other major vascular adverse events, which will bring adverse effects on the prognosis of patients (41). CDDP can inhibit platelet aggregation, reduce inflammation and damage of vascular endothelium. At present, a number of studies have evaluated the reduction of CDDP in the incidence of cardiovascular adverse events after PCI (42). Rong Y et al. observed that CDDP preconditioning could decrease the incidence of CIN in patients with PCI. Thus, CDDP is an appropriate adjuvant drug therapy before PCI (1). Zhang Y et al. also confirmed that CDDP could decrease CIN incidence in patients with PCI and the incidence of major cardiovascular adverse events (43). These were similar to our findings. Simultaneously, the mechanism of reducing the incidence of CIN by CDDP was further discussed, which could be connected with reducing inflammation and oxidative stress.

Our study has some limitations. First, we excluded patients with severe renal insufficiency and those who received CM 14 days before the procedure, as well as patients with severe cardiac insufficiency, heart failure, malignant tumors, fever, and emergency PCI. Second, the study was a single center with participants from the same hospital.