As an important part of the implementation of modern interventional techniques, contrast has played an important role in the interventional treatment of cardiovascular diseases. With the promotion and development of interventional techniques for cardiovascular diseases, the use of contrast agents is becoming more and more widespread, but the incidence of contrast nephropathy (Contrast-inducedpnephropathy, CIN) is increasing year by year, which has become one of the main issues of clinical concern for the safety of contrast agent application.
1.Diagnosis of CIN
CIN refers to the new onset of renal insufficiency after the application of contrast agents without other explanations, or the deterioration of renal function in those with existing renal insufficiency. The 2006 European Society of Genitourinary Radiology Contrast Guidelines define CIN as, among other factors, new or worsening renal impairment after intravascular contrast, commonly defined quantitatively as an increase in Scr (serum creatinine) of ≥44.2 umol/l (or 0.5 mg/dl) within 72 h of contrast administration or an increase of more than 25%.
Recently, it has been proposed that applying the estimated glomerular filtration rate (eGFR) or changes in serum cysteine proteinase inhibitor C as diagnostic indicators of CIN seems to be more accurate and sensitive, and some scholars have also investigated specific urinary markers after contrast by urinary proteomics with the aim of early diagnosis of CIN. however, changes in SCr before and after contrast are still the most commonly used clinically recognized and commonly used CIN measure. The expert consensus on contrast nephropathy in China adopts the definition of CIN from the 2006 European Society of Genitourinary Radiology contrast guidelines.
CIN not only significantly prolongs patients’ hospital stay and increases medical costs, but also significantly increases mortality, especially the cumulative annual mortality rate of those requiring dialysis due to CIN after contrast application is as high as 45%. In the last decade or so, the understanding of CIN has progressed positively and the incidence of CIN has decreased from approximately 15% to 7% due to appropriate measures. However, a study by Nash et al. found that CIN has become the third most common cause of hospital-acquired renal failure after renal underperfusion and nephrotoxic drug-induced renal failure.
2. Mechanism of CIN occurrence
CIN is mostly manifested as non-oliguric acute kidney injury (AKI). SCr levels usually rise 24-48 hours after imaging and reach a peak in 3-5 days, and some patients show transient urinalysis abnormalities, decreased urinary osmolality, elevated urinary enzymes, increased urinary glucose and urinary sodium excretion, etc. Most patients recover their renal function to the original level 7-10 days after imaging. Therefore, if renal function tests and urinalysis are not performed within 1 week after contrast, CIN is highly likely to be missed. about 20% of patients with CIN present with oliguric AKI, and the duration of oliguria and the degree of elevated SCr levels depend on the patient’s basal renal function level. about 30% of patients remain with varying degrees of renal insufficiency, and less than 1% of patients require maintenance renal replacement therapy.
The mechanisms of nephrotoxic effects of contrast agents include the following three aspects: direct chemical toxicity of contrast agents (ionic and iodine-containing substances), osmotic toxicity, and viscosity-related toxicity in the components. There is not enough evidence to reach a final consensus on the effects related to nephrotoxicity. However, osmolarity and viscosity are important factors contributing to the development of contrast nephropathy.
After contrast application, renal vessels first dilate briefly for 20 minutes and then contract spasmodically for 4 hours or longer. The above-mentioned phenomenon, on the one hand, leads to a blood-stealing effect on renal blood flow, i.e., blood flow from the relatively hypoxic renal medulla to the renal cortex, thus aggravating renal medullary ischemia and reducing oxygen supply; on the other hand, contrast agents, through their osmotic diuretic effect, can increase extramedullary sodium absorption and transport, raising the metabolic volume and oxygen demand of the renal medulla, further aggravating medullary ischemic and hypoxic injury. Studies have shown that adenosine, endothelin and free radicals, which cause vasoconstriction, are increased during this process, while nitric oxide and prostaglandins, which diastize blood vessels, are correspondingly reduced.
Focal or diffuse proximal tubular cytoplasmic vacuole formation on renal tissue biopsy after application of hyperosmotic contrast agents is the most direct evidence of contrast agent nephrotoxicity and a histological feature of osmotic nephropathy. Contrast agents increase oxygen radical production by decreasing renal cortical antihydrogenase and superoxide dismutase activities, in addition to increasing oxygen radicals themselves. In addition, hyperosmotic contrast agents can disrupt epithelial cell integrity, block renal tubules, and lead to immune responses.
Under normal conditions, the intra-tubular fluid viscosity is lower than that of plasma, and the use of highly viscous contrast agents (especially dimeric isotonic contrast agents) increases fluid resistance in the collecting tubules and intra-tubular pressure, resulting in a decrease in glomerular filtration rate and medullary blood flow. Contrast agents may even lead to tubular occlusion, which may affect renal filtration function. It has been shown that the viscosity with isotonic contrast agents is more temperature dependent than with hypertonic and hypotonic contrast agents. At 14°C, isotonic contrast viscosity increased twice as much as hypertonic or hypotonic contrast, whereas the difference between the three was not significant at 37°C.
A meta-analysis of 17 studies of vascular contrast agents in high-risk patients showed that the risk of contrast nephropathy was comparable with the use of the isotonic contrast agent iodixanol (iodixanol) and the hypotonic contrast agent iopamidol (iopamidol), but both were significantly lower than iohexol (iohexol). Although the osmolarity of iohexol and iopamidol were similar, the incidence of contrast nephropathy was significantly higher with iohexol than with iopamidol, suggesting that factors other than osmolarity are involved in contrast nephropathy due to an osmolarity ≤800NmOsm/kg contrast agent.
It was shown that the hyperosmotic contrast agent iothalamate significantly decreased renal medullary oxygen partial pressure to 1/3 of the control group, and that the isotonic contrast agent iotrolan was more likely to decrease local oxygen partial pressure than the hypotonic contrast agent iopromide. An analysis of the development of contrast nephropathy in 57925 patients who underwent coronary examination with isotonic or hypotonic contrast agents revealed that the isotonic contrast agent iodixanol had a higher probability of causing contrast nephropathy compared with the ionic hypotonic contrast agent ioclate (ioxaglate) and the nonionic contrast agent iohexol.
3. Risk factors for the development of CIN
Risk factors for CIN include: renal insufficiency, diabetes mellitus, factors during contrast (multiple lesions, increased contrast dose, application of aortic balloon counterpulsation), congestive heart failure (NYHA class III-IV), advanced age (>75 years), anemia, acute coronary syndrome, and low hematocrit. In 2004, Mehran et al. established a scoring system (i.e. MehranRisk Score, MRS) for risk factors of CIN, in which eGFR <20ml/min?1.73m2 was scored as 6, 20-40 as 4, 40-60 as 2, and hypotension as 2. 2 points for ~60, 5 points for hypotension (systolic blood pressure <80 mmHg for at least 1 h and requiring systolic augmentation), chronic renal insufficiency, congestive heart failure (NYHA class III-IV or history of pulmonary edema) and IABP, 4 points for age >75 years, 3 points for diabetes mellitus and anemia, 1 point for each additional 100 ml of contrast agent, and 4 points for Scr >1.5 mg/dl. The risk of CIN was 26.1% and the risk of hemodialysis was 1.09% when the risk score was 11-16, and 57.3% for CIN and 12.6% for hemodialysis when the risk score was ≥16, 26.1% and 1.09% for 11-16, and 14.0% and 0.12% for 6-10, respectively. MRS has been shown to have a significant impact on the risk of contrast nephropathy after non-emergent percutaneous coronary intervention. MRS is clinically relevant in predicting contrast nephropathy after non-emergent percutaneous coronary intervention. 15.5% and 13.5% at high risk (11-15 points), 5.5% and 5.7% at intermediate risk (6-10 points), and 1.9% and 2% at low risk (≤5 points) for predicting CIN requiring dialysis and mortality after 1 year, respectively.
(1) Renal function impairment
All multifactorial analyses showed that basal renal impairment was an independent predictor of CIN. Basal renal impairment (estimated glomerular filtration rate, eGFR < 60 ml/min/1.73 m2) is the most important predictor of the risk of CIN in patients undergoing iodine contrast. Therefore, it is important to assess basal renal function before applying iodine contrast to ensure an appropriate strategy to reduce the risk of CIN. Serum creatinine levels alone are not sufficient to accurately assess renal function, and clinicians need to calculate eGFR values based on serum creatinine as an indicator of renal function, rather than solely on blood creatinine levels. eGFR <60 to mL/min (equivalent to 1.3 mg/dL or 115 umol/L for men and 1.0 mg/dL or 88.4 umol/L for women) The risk of CIN is significantly higher in patients with CIN (1.0 mg/dL or 88.4 umol/L for women), and special care should be taken.
(2) Diabetes mellitus
The vast majority of studies have shown that diabetes is a predictor of CIN, and most (although not all) of these studies have found diabetes to be an independent predictor of CIN by multifactorial analysis. However, it is not clear whether the risk of CIN is increased in patients with diabetes mellitus without renal impairment.
(3) Contrast agent dosage
The occurrence of CIN is related to the amount of contrast agent used, but the relationship is threshold rather than linear. Cigarroa et al. recommended a maximum contrast dose of 5 ml x body weight (kg)/Scr (mg/dl) for patients with renal insufficiency, generally not exceeding 300 ml. Contrast doses exceeding 300 ml are an independent risk factor for CIN. Mehran et al. found that the risk of CIN in the general population increased by 12% for every 100 ml of contrast. in a study of 1500 patients undergoing PCI with concomitant diabetes, the rate of concomitant CIN was much higher in those with a contrast dose greater than 600 ml than in the low-dose group. (4) Heart failure
(4) Heart failure
The risk of CIN is also a risk factor for congestive heart failure, especially in those with cardiac function ≥ grade III or reduced left ventricular ejection fraction (LVEF), and Dangas et al. showed that LVEF > 30% had no effect on the development of CIN.
(5) Hyperuricemia
Earlier studies suggested that hyperuricemia was a contributing factor to CIN, but it was never proven to be an independent risk factor for CIN. A recent prospective cohort study of 266 patients who underwent coronary angiography found that the risk of CIN was 15.1% and 2.9% in those with hyperuricemia and normal uric acid, respectively, and that the risk of CIN was significantly higher in patients with hyperuricemia. Serum uric acid levels ≥7 mg/dl in men or serum uric acid water in women (6) Hypovolemia and low hematocrit
Low baseline hematocrit and perioperative decrease in red blood cell pressure are important risk factors. The lowest baseline hematocrit for men and women with increased risk of CIN was 38.4% and 34.4%, respectively. For every 3% decrease in basal hematocrit, the likelihood of CIN increased by 11% or 23% in those with or without underlying renal impairment, respectively. The current hydration therapy prevents the occurrence of CIN and confirms on the other hand that hypovolemia is a risk factor for the development of CIN.
(7) Advanced age
The high incidence of CIN in advanced age (>75 years) may be due to multiple factors, including reduced GFR, reduced renal tubular concentrations, and the presence of multiple vascular diseases.
(8) Intra-aortic ballon pump (IA BP)
IABP may induce CIN because the balloon can bring cholesterol microemboli from the aorta into the kidney, and patients undergoing IABP are often hemodynamically unstable.
(9) Other risk factors
Other risk factors include coronary artery bypass grafting, delayed coronary reperfusion, trauma, pulmonary edema, and acute respiratory distress syndrome. Risk factors have a cumulative effect, and an increase in the number of risk factors will lead to a dramatic increase in the risk of CIN. The risk of CIN in patients with multiple risk factors is as high as 50%.
4.Prevention and treatment of CIN
In view of the serious consequences that CIN may bring, the Chinese CIN expert consensus advocates that the focus should be on prevention. The results of previous studies show that perioperative hydration therapy is currently an effective therapeutic measure to prevent the occurrence of CIN. Hydration can increase renal blood flow, reduce renal vasoconstriction, reduce the residence time of contrast agents in the kidney, improve the flow of uric acid in the renal tubules, reduce the formation of tubular patterns, and exert beneficial effects of neurohormones, thus reducing the incidence of contrast nephropathy. The currently accepted fluid of choice for hydration therapy is isotonic saline. And intravenous hydration is significantly more effective than oral rehydration.
The possible role of reactive oxygen radicals in the pathogenesis of CIN has led to an assessment of the role of the oxidative inhibitor N-acetylcysteine (NAC) in CIN. the pharmacological mechanism of NAC has many attractions and is theoretically effective in preventing contrast nephropathy, but in a meta-analysis NAC was shown to be controversial for the prevention of contrast nephropathy. It is currently considered to be a neutral-acting drug. However, the REMEDIAL study showed that sodium bicarbonate, a drug that has no advantage alone, was surprisingly effective when combined with NAC – significantly better than saline combined with NAC – suggesting that we should reconsider the effectiveness of drug combinations.
The incidence of statin prevention of CIN has shown promising signs. A 2005 retrospective analysis evaluating the effect of statins on the incidence of CIN reported that the incidence of CIN in the preoperative statin group of 29,409 patients treated with PCI was nearly 4.37%, much lower than that in the group without preoperative statin intervention (5.93%). (5.93%). In 2008, when evaluating the effect of preoperative statin therapy on CIN in patients undergoing PCI at the Fu Wai Cardiovascular Hospital in China, it was found that preoperative statin intervention resulted in a significantly lower risk of postoperative CIN (7.1% vs. 20.6%) and that statin “pretreatment” was an independent predictor of CIN by multifactorial regression analysis. The multifactorial regression analysis indicated that statin “pretreatment” was an independent predictor of CIN.
Previous studies on trimetazidine have focused on anti-myocardial ischemia and improvement of cardiac function, while clinical studies on trimetazidine in contrast nephropathy are scarce. In vivo experiments have confirmed that trimetazidine has anti-oxidative stress effects when ischemic renal injury is present; when renal blood flow is reduced, trimetazidine increases renal medullary blood flow and improves ischemic renal injury. Existing studies have confirmed that in patients with chronic renal insufficiency, oral trimetazidine with hydration significantly reduces the incidence of contrast nephropathy during intracoronary intervention, and this finding may be related to the antioxidant stress effect of trimetazidine and increased renal medullary blood flow.
In addition, calcium channel blockers, atrial natriuretic peptide, L-arginine, and tachykininin are selective therapeutic measures, as well as dialysis treatment when necessary. The preventive effect on CIN is mostly neutral results or negative, while the value of prophylactic hemodialysis in the prevention of CIN still has to be verified in large-scale clinical studies.
Conclusion
In the current clinical setting where hypotonic contrast is widely used, the pathogenesis of CIN needs to be further investigated in depth. The uncertainty in the outcome of isotonic contrast agents in reducing the incidence of CIN prompts that the interaction between osmolality and viscosity in the pathogenesis of CIN should be investigated in depth.