Contrast-induced nephropathy: searching for new solutions to prevent its development

Contrast-induced nephropathy (CIN) is the main cause of acute kidney injury and worsens the prognosis of chronic kidney disease. To evaluate the clinical risk score of CIN development, various medical calculators are proposed. The main criterion for assessing the possible development of CIN is the initial glomerular filtration rate presented by estimated glomerular filtration rate. Toxic effect of contrast substances is realized through the properties of the molecule of contrast itself (tubular cell damage) and induced ischemia with oxidative stress and vasoconstriction. Existing methods for preventing the development of CIN are based on reducing the toxic effect of a contrast agent and preventing hypoxic kidney shock. The drugs currently proposed are acetylcysteine, statins, and some other approaches as well as hemodialysis. However, the evidence base is the most informative for hydration, which should be used before the introduction of a contrast agent, along with the minimization of the dose of contrast. Nevertheless, no final solution has been found to prevent the development of CIN. We have proposed the use of edaravone, which has an evidence base for ischemic stroke, to prevent the development of CIN. Three patients with chronic kidney disease stage 3b were given 30 mg edaravone twice a day before contrast media infusion and during two days after contrast administration. In two patients, CIN was avoided. The proposed approach requires future research to evaluate its effectiveness.

Contrast-induced nephropathy (CIN) is the major cause of acute kidney injury in chronic kidney disease (CKD) [1] and a third most common cause of acute kidney injury (AKI) in hospitalized patients following volume depletion and medication [2].
Contrast-induced nephropathy is defined as the impairment of renal function measured as either a 25% increase in serum creatinine from baseline or a 0.5 mg/dL (44 µmol/L) increase in absolute serum creatinine value within 48-72 hours after intravenous contrast administration [3].
Several guidelines provide CIN patient surveillance; one of the latest (2018) is represented by the European Society of Urogenital Radiology (ESUR) [5] that defines post-con-trast acute kidney injury as an increase in serum creatinine ≥ 0.3 mg/dl (or ≥ 26.5 µmol/l), or ≥ 1.5 times from baseline, within 48-72 h of intravascular administration of contrast medium (СМ).
The key recommendations of this guideline are the following:

Nephrotoxic medication
In CKD patients receiving CM, optimal nephrology care involves minimizing the use of nephrotoxic drugs (level of evidence А).
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers do not have to be stopped before CM administration (level of evidence D).
There is insufficient evidence to recommend withholding nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs, antimicrobial agents or chemotherapeutic agents before CM administration (level of evidence B).

Hydration
Preventive hydration should be used to reduce the incidence of post-contrast acute kidney injury in patients at risk (level of evidence B).
Intravenous saline and bicarbonate protocols have similar efficacy for hydration (level of evidence A).
For intravenous and intra-arterial CM administration with the second pass renal exposure, hydrate the patient with either: a) 3 mL/kg/h 1.4% bicarbonate (or 154 mmol/L solution) for 1 h before CM; or b) 1 mL/kg/h 0.9% saline for 3-4 h before and 4-6 h after CM (level of evidence D).
For intra-arterial CM administration with the first pass renal exposure, hydrate the patient with either: a) 3 mL/kg/h 1.4% bicarbonate (or 154 mmol/L solution) for 1 h before CM followed by 1 mL/kg/h 1.4% bicarbonate (or 154 mmol/L) for 4-6 h after CM; or b) 1 mL/kg/h 0.9% saline for 3-4 h before and 4-6 h after CM (level of evidence D).
Oral hydration as the sole means of prevention is not recommended (level of evidence D).
No other drug recommendations (acetylcysteine, statins) and dialysis for CIN prevention were presented in the guidelines; it is associated with their poor evidential base. However, a positive effect of nebivolol that is used to reduce the risk of CIN and is prescribed before contrast study was not evaluated [6].
An important aspect is also the absence of the need to prescribe diuretics both in CIN and in acute kidney injury (see below) [7].

Sudden stop of diuresis:
-acute kidney injury: diuretics are contraindicated, euvolemia maintenance is recommended.

Chronic fluid retention:
-chronic kidney disease: long-term diuretic therapy is indicated (loop diuretics and aldosterone antagonists), vascular hypovolemia should be avoided.
Before deciding to perform PCI, our clinic has chosen the following algorithm (Table 1).
Therefore, nowadays the only method of CIN prevention is hydration [5,8], and risks are determined by glome rular filtration rate and by the state of the cardiovascular system.
Toxic effect of contrast substances is realized through: 1) properties of the molecule of contrast itself (tubular cell damage); 2) induced ischemia with oxidative stress and vasoconstriction [9].
Serum creatinine levels peaking 2-3 days after administration of contrast medium and returning to baseline within 7-10 days after administration are accompanied by ischemic changes [10].
While evaluating CIN pathogenesis, our attention was paid to another aspect about ischemia -the successful use of edaravone, an agent blocking the ischemic cascade; nowa days, it is used for treatment of acute ischemic stroke [11]. It is to be recalled some facts about edaravone: -this agent was involved in clinical studies with a high level of evidence that have been conducted in Japan since 2001; -every third patient having received the drug during the first 24 hours after onset of ischemia will have no consequence of stroke at all; -this is the first drug over the past 23 years that is approved by the Food and Drug Administration in 2017 for treatment of amyotrophic lateral sclerosis [12].
In our clinic, three patients with stage 3b CKD have received 30 mg of edaravone (Xavron, Ukraine) intravenously twice a day before PCI and two days after the procedure. Development of CIN was observed in one patient; two patients have shown less than a 1.5-fold increase in serum creatinine level during 5 days of monitoring.
We believe that the initiation of use of edaravone for CIN prevention provides a clinical perspective. Nevertheless, future trials need to be done to prove the possibility of preventing CIN with edaravone.

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