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Nazar M. A. Mohammed

1Department of Cardiology, Heart Hospital, Hamad Medical Corporation, Doha, Qatar


Address for correspondence: Dr. Nazar A. Mohammed, Department of Cardiology, Heart hospital, Hamad Medical Corporation, Doha, PO BOX 3050, Qatar. E-mail: moc.liamg
This is an open-access article distributed under the terms of the Creative sầu Commons Attribution-Noncommercial-Share Alượt thích 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Bạn đang xem: By contrast là gì


Contrast-induced nephropathy (CIN) is a serious complication of angiographic procedures resulting from the administration of contrast truyền thông media (CM). It is the third most comtháng cause of hospital acquired ađáng yêu renal injury & represents about 12% of the cases. CIN is defined as an elevation of serum creatinine (Scr) of more than 25% or ≥0.5 mg/dl (44 μmol/l) from baseline within 48 h. More sensitive sầu markers of renal injury are desired, therefore, several biomarkers of tubular injury are under evaluation. Multiple risk factors may contribute to the development of CIN; these factors are divided inlớn patient- và procedure-related factors. Treatment of CIN is mainly supportive sầu, consisting mainly of careful fluid & electrolyte management, although dialysis may be required in some cases. The available treatment option makes prevention the corner stone of management. This article will Review the recent evidence concerning CIN incidence, diagnosis, và prevention strategies as well as its treatment and prognostic implications.


Keywords: Contrast-induced nephropathy, definition, management of contrast-induced nephropathy, risk scoring và stratifications

INTRODUCTION

Contrast-induced nephropathy (CIN) is a serious complication of angiographic procedures & results from administration of iodinated contrast media (CM).<1,2,3>

CIN is the third most common cause of hospital acquired acute renal injury representing about 12% of the cases. The incidence of CIN varies between 0 và 24% depending on patient"s risk factors.<4> It is generally a transient & reversible size of axinh đẹp renal failure.<5> However, the development of CIN is associated with a longer hospital stay, an increased morbidity and mortality, in addition khổng lồ a higher financial cost.

Treatment of CIN is mainly supportive sầu, consisting of careful fluid và electrolyte management, although dialysis may be required in some cases.<6> The limitation in the available treatment options makes prevention the cornerstone of management.

This article will Đánh Giá the recent evidence concerning CIN incidence, diagnosis, & prevention strategies as well as its treatment & prognostic implications.


Definition

CIN is defined as an elevation of serum creatinine (Scr) of more than 25% or ≥0.5 mg/dl (44 μmol/l) from baseline within 48 h after excluding other factors that may cause nephropathy, such as nephrotoxins, hypotension, urinary obstruction, or atheromatous emboli. It is self-limited in most instances, with Scr levels peaking in 3-5 days and gradually returning to baseline levels within 7-10 days.<7,8,9>


Prevalence

CIN is one of the major causes of hospital-acquired axinh tươi kidney injury (AKI)<10> và represents about 12% of the cases.<11> It is the third most comtháng cause after renal hypoperfusion (42%) và postoperative renal injury (18%).

The reported incidence of CIN after percutaneous coronary intervention (PCI) varies between 0 and 24%, depending on the prevalence of associated risk factors, with the higher incidence being reported after emergency PCI.<12,13,14,15>

A meta-analysis that included 40 studies, found a 6% incidence of CIN after contrast enhanced computed tomography (CT),<16> 9% after peripheral angiography,<17> và 4% after intravenous pyelography.<18>

The incidence of CIN is low in patients with normal renal function (0-5%).<19> However, several prospective controlled trials reported an incidence of 12-27% in patients with preexisting renal impairment.<7,19,20> Furthermore, in one study, an incidence as high as 50% was reported in patients with diabetic nephropathy undergoing coronary angiography in spite of the use of low-osmolar CM (LOCM) & adequate hydration. Notably, up to lớn 15% of them required dialysis.<21> Development of CIN is associated with a longer hospital stay, an increased morbidity và mortality, in addition khổng lồ a higher cost.<1,2,3>

Elevation of post-PCI Scr may have prognostic significance regardless of initial kidney function. In fact, even a slight elevation in Scr (25-35 μmol/l) is associated with an increase in 30-day mortality.<22> Furthermore, post-PCI Scr elevation has been reported to lớn be associated with a higher 1-year mortality than periprocedural myonecrosis.<23>


THE PATHOPHYSIOLOGY

Although the definite mechanism of CIN is not well-understood, several mechanisms have sầu been proposed

Renal medullary hypoxia due lớn either a decrease in vasodilators (nitric oxide or prostaglandins), or an increase in vasoconstrictors (adenosine và endothelin).


Risk factors

Multiple risk factors may contribute to lớn the development of CIN; these factors are divided inkhổng lồ two groups; patient- & procedure-related.

Preexisting renal insufficiency (estimated glomerular filtration rate (eGFR) <60 ml/min) và diabetes mellitus are the most important patient-related risk factors. Others, include age >75 years, uncontrolled hypertension, hypotension requiring inotropes, congestive heart failure (CHF), use of intra-aortic balloon pump (IABP), anemia, hypoalbuminemia, và liver cirrhosis.

Procedure-related factors include high contrast volume, osmolality or viscosity, and repeated exposures to lớn CM within 72 h. Other factors that may increase the risk of CIN include the concomitant use of diuretics or nephrotoxic drugs (nonsteroidal anti-inflammatory drugs (NSAIDs) and aminoglycosides).<11,27,28,31,32,33>


RISK SCORING AND STRATIFICATIONS

Several risk stratification scoring systems have been developed to lớn assess the risk of developing CIN.<33,34,35,36> One of the main goals of these scoring systems is khổng lồ help clinicians and patients weigh the risk of the exposure versus its benefit.

Bartholomew and his colleagues used a database of đôi mươi,479 patients khổng lồ develop a risk scoring system of eight variables (creatinine clearance <60 ml/min, use of IABPhường, urgent coronary procedure, diabetes, CHF, hypertension, peripheral vascular disease, & contrast volume). In this scoring system, the population with the highest risk score had a 28% incidence of CIN & a 17% risk of death.<35>

Mehran et al., used a database of 8,357 interventional cardiology patients (mean age 63.6 years, 28.8% females) to lớn develop a CIN risk scoring system. This system is based on eight variables: i) hypotension for more than 1 h requiring inotropes, ii) use of IABPhường within 24 h of the procedure, iii) CHF New York Heart Association (NYHA) class III or IV, iv) age >75 years, v) anemia with hematocrit value <39% for men và <36% for women, vi) diabetes mellitus, vii) contrast volume (1 point for each 100 ml), & viii) baseline Scr >1.5 mg/dl (132 μmol/l). The incidence of CIN và dialysis increased with higher risk score (CIN incidence; 7.5, 14, 26.1, and 57.3%) if total risk score ≤5 (low), 6-10 (moderate), 11-16 (high), & ≥16 (very high), respectively.<33> Of note, no prospective validation of published risk scores has been done.


Diagnosis

Elevation of Scr of more than 25% above baseline and within 48 h post CM administration is the key diagnostic criteria after excluding other causes. Additional laboratory findings such as acidosis and/or hyperkalemia may be present. In regards to urine output; patient may be oliguric, anuric, or have sầu normal urine output. Findings on urine examination are usually nonspecific.<36>

There is usually a 24-48 h delay between contrast exposure & the change in Scr. This delay makes creatinine a late indicator of renal function changes,<37> therefore more sensitive markers of renal injury are desirable. In fact, several biomarkers of tubular injury have sầu been under evaluation


Treatment

There is no definitive treatment available for established CIN; therefore, the benefit for CM-based diagnostic studies or interventional procedures should always be weighed against the risk of CIN. In addition, repeated exposure lớn CM within a short period of time should be avoided whenever possible.


Prevention strategies

Several pharmacological & nonpharmacological approaches have been evaluated for the prevention of CIN. The prevention strategies are most important in patients at high risk for CIN, such as those with AKI or preexisting chronic kidney disease (CKD). It is well established that minimizing the volume of CM, preventing volume depletion & avoiding activation of renal vasoconstriction are the most effective measures to lớn prevent CIN. In addition, the concomitant use of diuretics or nephrotoxins (e.g. nonsteroidal anti-inflammatory drugs (NSAIDs), cytotoxic drugs, & aminoglycosides) should be avoided.<4>


NONPHARMACOLOGICAL APPROACH


Contrast medium related factors

CM is a diagnostic iodinated material used to lớn enhance the visibility of blood vessels. It is mainly excreted through the kidneys with less than 1% eliminated via extrarenal routes in patients with normal kidney function.<48> The half-life of CM is about 2 h with 75% excreted within 4 h & 98% within 24 h.<49,50>

In the renal tubules, the excreted CM generates osmotic force causing marked increase in sodium và water excretion. This diuresis will increase intratubular pressure, which will reduce the GFR, contributing khổng lồ the pathogenesis of acute renal failure.<51> The effect of CM on the kidney depends on its volume, osmolality, và viscosity.

CM volume is a risk factor for CIN, correlation between the CM volume và risk of CIN was investigated in patients at high-risk for CIN.

Brown & his group attempted to identify the relationship between CM volumes, body toàn thân weight, and baseline renal function in patients who received CM, with a goal to identify a maximum acceptable contrast dose (MACD). MACD was determined by the following formula: (Contrast ml = 5 × body toàn thân weight (kg))/(88.4 × SCr (μmol/l)). They concluded that patients who received CM volumes more than the calculated MACD had a higher incidence of CIN & dialysis requirement than those who did not exceed the calculated MACD.<52> Nyman, et al., studied the relation between CM dose (Gram"s iodine; GI), estimated GFR (eGFR; ml/min), and the incidence of CIN in patients who underwent primary PCI following ST-segment elevation adễ thương myocardial infarction. The study showed that CIN incidence increased with high CM dose/eGFR ratio.<53> McCullough et al., found that the risk of CIN is low in patients with normal kidney function receiving less than 100 ml of CM.<1> However, the risk remains high in patients with CKD receiving less than 100 ml of CM with possible need for dialysis or progression khổng lồ end-stage renal disease.<21,54>

LOCM is more expensive than high-osmolar one và it has been shown khổng lồ lower the incidence of CIN. Nevertheless, there has been no significant difference between high-osmolar & low-osmolar iodinated CM in patients with normal kidney function. The nephrotoxic effect of high osmolar CM is higher in patients with preexisting CKD or in the presence of significant risk factors for CIN.<đôi mươi,55,56>

The benefit of iso-osmolar CM (IOCM) over LOCM in patients with preexisting CKD or those at high risk for CIN is debatable. Some clinical trials found no benefit of nonionic IOCM (i.e. iodixanol) compared to lớn nonionic LOCM (i.e. iopamidol, iopromide, ioversal, iomeprol, iobitridol, và iopentol),<21,57,58,59,60,61,62,63> while other trials found reduction in the incidence of CIN with IOCM (i.e. iodixanol) compared lớn nonionic LOCM (i.e. iohexol, iopromide, and ioxaglate).<64,65,66> It appears that iohexol, iopromide, & ioxaglate have a higher incidence of CIN than other LOCM, while no similar data are available for the nonionic LOCM.

It has been initially thought gadolinium-based CM would be safer than iodinated CM in patients with preexisting CKD or those at high risk for CIN.<67> Nevertheless, case reports & small studies reported evidence of nephrotoxithành phố using gadolinium-based CM, especially when used in high doses in patients with preexisting CKD or those at high risk for CIN. A long half-life of gadolinium-based CM and its lower clearance due to lớn a small volume of distribution (Vd), and its excretion through glomerular filtration may contribute to lớn the nephrotoxic effect.<68,69,70,71,72> More importantly, gadolinium-based CM have sầu been associated with the development of nephrogenic systemic fibrosis in patients with significant decrease in GFR. Therefore, its use is contraindicated in patients with GFR less than 30 ml/min/1.73 mét vuông and it should be used with caution in patients with GFR between 30 & 60 ml/min/1.73 m2.<73> Gadolinium-based CM might be a reasonable option in patients with severe allergy to lớn iodine or iodine CM.<74>


HEMODIALYSIS AND HEMOFILTRATION

Intermittent hemodialysis or peritoneal dialysis has been shown to efficiently remove sầu CM from the circulation; several studies have been carried out lớn evaluate the effectiveness of prophylaxis dialysis strategy.<75,76> A study by Lee et al., showed a protective effect,<77> all other clinical trials did not find any benefit of immediate hemodialysis after exposure to lớn CM in patients with preexisting CKD undergoing angiography.<78,79,80>

Hemofiltration is another preventive sầu strategy that have sầu been studied for CIN prevention in patients at high risk.

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<81,82,83> Marenzi et al., found that periprocedural hemofiltration for 24 h after CM exposure was an effective sầu strategy for the prevention of CIN in patients with preexisting CKD leading lớn a decrease in the in-hospital mortality and a better long-term outcomes.<84> However, these modalities are not yet supported with sufficient evidence. Additionally, these modalities require intensive sầu care unit (ICU) admission and may not be practical in most settings.


Volume expansion

Volume expansion is the most effective sầu strategy in prevention of CIN. The exact mechanism by which volume expansion reduces the risk of CIN is not well-known. One possible mechanism is the dilution of CM by more fluid reduces the concentration of CM và subsequently it may minimize the risk of CM exposure và reduce the nephrotxic effect. Another possible mechanism is that volume expansion reduces the intrarenal hemodynamic alterations by inhibition of renin-angiotensin-aldosterone system (RAAS) minimizing the renal vasoconstriction.<85,86>

Multiple randomized controlled trials were performed in the past đôi mươi years and confirmed the beneficial role of intravenous fluid administration in the prevention of CIN.<87,88,89,90> In several recent trials, the common approach for adequate intravenous volume expansion was isotonic saline (0.9% NaCl) or hypotonic saline (0.45% NaCl) at a rate of (1.0-1.5 ml/kg/h) for 3-12 h prior the procedure & continued for 6-24 h after the procedure aiming khổng lồ maintain the urine flow rate more than 150 ml/h.<91,92> One study compared isotonic saline (0.9% NaCl) with half saline in dextrose 5% water (D5W 0.45% NaCl) in patients undergoing elective or emergency coronary angioplasty. In this study, the incidence of CIN was significantly less with isotonic saline than hypotonic saline.<89>

The renoprotective effects of oral and intravenous administration of fluids were compared in patients at high risk for CIN. One randomized trial showed no difference in the incidence of CIN between the two routes.<93> However, another trial (n = 53) found a lower incidence of CIN in patients receiving intravenous saline than those received fluids orally.<94> In a recent observational study, the effects of oral fluid intake in patients undergoing CT angiography that had normal kidney function was closely correlated with the percentage changes in SCr and the absolute changes in eGFR.<95>

Patients with CKD & left ventricular dysfunction (left ventricular (LV) ejection fraction <40%), are at increased risk for volume overload. Therefore, volume expansion should be done after a careful assessment of clinical and volume status.


Sodium bicarbonate

Sodium bicarbonate may reduce the risk of CIN by decreasing miễn phí radicals formation through an alkaline pH that reduces the production and increases the neutralization of oxygene.<96,97,98>

Nevertheless, conflicting results were derived from the clinical trials on the efficacy of sodium bicarbonate. In several clinical trials & meta-analyses; intravenous sodium bicarbonate showed a significant risk reduction of CIN compared lớn intravenous isotonic saline with or without N-acetylcysteine (NAC), even though there was no difference in the need for dialysis, in-hospital mortality, or heart failure.<87,90,99,100,101,102,103,104>

Meanwhile, other studies, published and unpublished<105,106> did not show any beneficial effect. This included a prospective sầu randomized trial comparing sodium bicarbonate lớn isotonic saline with NAC in patients undergoing coronary angiography with creatinine clearance (CrCl) <60 ml/min.<107> Furthermore, one retrospective sầu cohort study conducted at Mayo clinic found that the incidence of CIN increased with intravenous sodium bicarbonate.<108>

In conclusion, the role of sodium bicarbonate in prevention of CIN is yet khổng lồ be determined, and the decision khổng lồ use sodium bicarbonate in the prevention of CIN should be made on an individual basis. A large prospective randomized multicenter trial is needed to lớn clarify this question.


N-Acetylcysteine

NAC has an antioxidant effect; scavenging oxygen-derived không tính tiền radicals, which may lead to lớn improved endothelium-dependent vasodilatation.<109,110>

Intravenous & oral NAC have sầu been studied in the prevention of CIN in patients with or without renal impairment. While NAC is indicated for the treatment of acetaminophen intoxication, it is not approved by the Food and Drug Administration (FDA) for the prevention of CIN. High intravenous doses of NAC (used in treatment of acetaminophen intoxication) may have detrimental effects on myocardium và the coagulation system.<111,112> In addition, high incidence of anaphylactoid reactions (up to 48%) and one death in an asthmatic patient have been reported.<113,114> However, when intravenous NAC is used for CIN prophylaxis, a much lower dose of 1,200 mg twice/day is the usual dose.<115>

The protective effect of NAC has been demonstrated in several clinical studies even though there were significant limitations in these trials, such as a relatively small sample size, heterogeneity, and publication bias.<116,117,118,119>

However, the enthusiasm for using NAC has faded away after a large randomized controlled trial và meta-analyses failed lớn show any added renoprotective benefit or efficacy of NAC in patients with CKD versus placebo.<12,120,121>

This large randomized trial, Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT), enrolled 2,308 patients undergoing coronary or peripheral vascular angiography with at least one risk factor (>70-year-old, diabetes mellitus, renal failure, heart failure, or hypotension). These patients were randomized to lớn receive sầu NAC (two doses of 1,200 mg before và two doses of 1,200 mg after angiographic procedure) versus placebo.

The incidence of CIN (primary endpoint) was 12.7% in the NAC group and 12.7% in the control group (relative sầu risk (RR), 1.00; 95% CI, 0.8đơn.25; P = 0.97). The same results were observed in all subgroups analyzed, including those with renal impairment.<12>


Ascorbic acid

Ascorbic acid is an antioxidant which has been studied in the prevention of CIN. One randomized controlled trial (n = 231) found that ascorbic acid reduced the incidence of CIN in patients undergoing coronary angiography in comparison with placebo.<122> However, another randomized double-blind trial (n = 143) failed to lớn show benefit of ascorbic acid in the prevention of CIN in patients with renal dysfunction.<123> A recently published randomized controlled trial (n = 212) compared a high dose of NAC to lớn a high dose of ascorbic acid in patients with renal dysfunction (CrCl < 60 ml/min) undergoing coronary angiography. The study found that the incidence of CIN was higher in patients receiving ascorbic acid than those who received NAC; however, the difference was not statistically significant.<124> Therefore, the use of ascorbic acid is not recommended in the prevention of CIN.


Theophylline

Theophylline is a xanthine derivative và a nonselective sầu adenosine receptor antagonist (A1 và A2). Oxygen consumption or decreased intracellular adenosine triphosphate (ATP) will lead lớn increase màn chơi of adenosine that will contribute khổng lồ afferent arteriolar vasoconstriction after CM exposure. Katholi et al.,<125> have sầu shown that theophylline prevented the decrease in GFR after CM exposure. These findings were supported by other trials.<126,127> Additionally, a recent study showed theophylline plus bicarbonate prophylaxis significantly reduced the incidence of CI-AKI compared lớn bicarbonate alone.<128> However, many recent clinical trials, meta-analyses, and systemic Reviews did not support the beneficial effect of theophylline in prevention of CIN.<129,130,131,132,133>

Since the results of studies using theophylline were inconsistent & the relevant clinical benefit is doubtful, current recommendation does not tư vấn its use in the prevention of CIN. In addition, there is the possibility of gastrointestinal, neurological & cardiovascular side effects with theophylline.


HMG CO A reductase inhibitors

The HMG-CoA reductase inhibitors (statins) are mainly used as cholesterol-lowering agents, but they are also known to have sầu antioxidative sầu và anti-inflammatory properties so they may reduce the risk of CIN.<134,135>

Some studies suggested that the chronic use of statin has a protective sầu effect against CIN, with a reduction in the incidence of dialysis and long-term mortality.<136,137>

In a recent systematic review & meta-analysis; chronic statin treatment (≥7 days) reduced the risk of CIN (P < 0.05), whereas a short-term high-dose therapy did not.<138>

Nevertheless, other studies have reported a null effect for statin use và an even higher incidence of CIN in the statin group.<139,140>

The role of statin use in preventing CIN is inconclusive sầu, and this could be attributed in part khổng lồ the variability of statin dosing & length of use.<141,142> A large controlled randomized trial is needed lớn assure the beneficial effect of statins in preventing CIN.


Calcium channel blockers

The data available for the use of CCBs is limited. CCBs are known lớn have an attenuating affect both the magnitude và duration of renal vasoconstriction after CM exposure, suggesting its potential benefit in reducing CIN.<143> In fact one trial showed a beneficial effect of starting CCBs shortly prior khổng lồ PCI in reducing CIN.<144> However, this benefit was not observed in other trials.<145,146>


Allopurinol

Allopurinol is a xanthine oxidase inhibitor which may limit the fall in the GFR after CM exposure by limiting oxygen-miễn phí radical formation, inhibiting adenine nucleotide degradation and by decreasing the vasodilatation response lớn intrarenal adenosine in the renal vasculature. In one study, allopurinol (4 mg/kg) was given orally starting 24 h before CM exposure & showed a protective sầu effect against CIN.<27>

A recent trial (n = 159) randomized patients undergoing coronary procedures (Scr > 1.1 mg/dl) lớn allopurinol (300 mg orally) with hydration or hydration alone. This trial found allopurinol may protect against CIN in high-risk patients receiving CM.<147>

The beneficial effect of allopurinol in the prevention of CIN needs further studies.


Fenoldopam

Fenoldopam mesylate is a selective dopamine-1 receptor agonist known lớn produce both systemic and renal arteriolar vasodilatation. It has been shown khổng lồ reduce the incidence of CIN in high risk patients undergoing PCI in one study;<148> however, a large randomized controlled trial (n = 52,315) failed to lớn show any protective effect against CIN.<149>


Dopamine

Dopamine (in a renal dose 0.5-2.5 μg/kg/min) has a dilatory effect on the renal vasculature and has an ability to increase renal blood flow và GFR with a potential benefit in the prevention of CIN. Positive sầu trials were small, non-randomized, inadequately powered, & with questionable end-points of clinical significance.<150>

On the other hvà, negative trial, were large, randomized, controlled, and with adequate statistical power;<151,152> therefore, the use of dopamine in prevention of CIN is no longer recommended.


Prostaglandin E1 (alprostadil)

Prostaglandin E1 is a well-known vasodilator that improves renal blood flow. It has shown some benefit in small clinical studies.<153,154> Nevertheless, the risk of CIN increased with higher infusion rate, likely due khổng lồ prostaglandin (PG)-induced hypotension. Further large trials are required to prove sầu the protective sầu effect and address the safety concerns.


Avoidance of nephrotoxic drugs

The comtháng potential nephrotoxic drugs include angiotensin converting enzymes inhibitors (ACEIs), angiotensin receptor antagonists, aminoglycosides, amphotericin B, diuretics, NSAIDs/cyclooxygenase (COX)-2 inhibitors, & antiviral drugs lượt thích acyclovir và foscarnet. The concomitant use of these drugs with CM administration should be avoided when possible in order to reduce the risk of CIN.<155>

Metformin is mainly eliminated via the kidneys (90%). As a result, metformin will accumulate in the sự kiện of AKI.<156,157> It is recommended that metformin should be held 24-48 h before CM exposure lớn avoid the risk of lactic acidosis và restarted when clinically appropriate (e.g. no development of CIN or when renal function returns lớn baseline).

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