Contrast induced nephropathy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

Contrast media (CM) are widely used in diagnostic and interventional procedures with rising incidence of iatrogenic renal function impairment caused by the exposure to contrast media, a condition known as contrast-induced nephropathy (CIN).

In 2012, a new definiton for contrast induced nephropathy was put forth by the KDIGO-AKI guidelines. CIN was to be considered a new form of acute kidney injury (AKI) caused by contrast media, and definition criteria for AKI would also apply for CIN now called contrast-induced acute kidney injury (CI-AKI).^[1] However, the most commonly used definition in clinical trails is acute renal insufficiency marked by an increase in baseline serum creatinine of >25% or an absolute increase in serum creatinine of 0.5 mg/dL that occurs 48-72 hours following the exposure to CM.^[2][3] The new definition shifted the 0.5 mg/dL cut-off to 0.3 mg/dL and the 25% increase in baseline to 1.5 times the original serum creatinine.

Most of data related to the contrast nephropathy come from animal models. Studies show evidence of acute tubular necrosis (ATN) but the mechanism by which ATN occurs is not well understood.

The pathophysiology of CIN is not clearly understood; however, several attempts have been made to explain the underlying mechanism. It is generally agreed that CIN is due to a combination of several influences brought on by contrast-media infusion rather than a single process. The most important mechanism thought to be involved in CIN is a reduction in renal perfusion and subsequent hypoxia. This has been attributed to several alterations in the renal microenvironment including activation of the tubuloglomerular feeback, local vasoactive metabolites including adenosine, prostaglandin, NO, and endothelin as well as increased interstitial pressure.^[4] Although sometimes considered controversial, studies have also proposed injury to renal tubular cells as another contributor both via a direct cytotoxic effect and via reactive oxygen species production.^[5]

The differential diagnosis includes atheroembolic renal failure, acute renal failure, acute interstitial nephritis, and acute tubular necrosis.

Incidence of CIN in the general population have been reported to be 0.6–2.3%.^[6] Considered to be the third most common cause of renal failure with overall mortality rate 19.4%, which is similar for all causes of renal insufficiency.^[7]

Many factors have been associated with an increased risk of nephropathy in patients exposed to contrast media. Pre-existing renal insufficiency, pre-existing diabetes, age, volume of CM, and reduced intravascular volume are examples for these risk factor.^[8][9] The total risk rises as the number of risk factors increase, it has been recommended that every known risk factor should be analyzed, to properly evaluate a total cumulative risk of developing contrast-induced nephropathy. A clinical prediction rule is available to estimate probability of nephropathy (increase ≥25% and/or ≥0.5 mg/dl in serum creatinine at 48 h).^[10]

CIN is often characterized by a transient increase in serum creatinine that peaks at 3 to 6 days after exposure to radiocontrast. Rarely, CIN leads to ESRD in patients with baseline kidney disease. CIN is also associated with increased risk for adverse cardiovascular events and a higher all-cause mortality. Prognosis is especially poor in patients that require hemodialysis after CIN.

Creatinine increase is the characteristic finding in CIN, kidney injury occur with in minutes of exposure to contrast agents, however clinical manifestations such as oliguria or elevation of serum creatinine are generally observed within 24 to 48 hours after contrast exposure.

Physical examination is helpful to differentiate other causes of acute nephropathy, examples for different presentations include rash in drug-induced interstitial nephritis, blue toe and livedo reticularis in case of embolism. Some risk factors can be detected as evidence of volume depletion, and decompensated CHF, and correcting these factors help improving the outcome.

Increase in the serum creatinine are generally observed within 24 to 48 hours after contrast exposure in most of patients, hyperkalemia, acidosis and hyperphosphatemia may be present.

Management of CIN routinely includes the avoidance of substances that are toxic to the kidneys. Dialysis is rarely required for AKI following contrast administration, but occasionally patients will require dialysis in the acute setting, the indications for dialysis are the same as in other forms of AKI.

Many strategies have aimed at preventing CIN. Non-therapeutic measures include smaller doses of contrast and use of low-osmolar or iso-osmolar agents. Several therapeutic measures have also been investigated notably volume expansion, N-acetylcysteine (NAC) , theophylline, statins, and fenoldopam. Evidence regarding the efficacy and benefit of each of these medical therapies has been contradictory although some have shown more promise than others. Currently only 2 therapies are indicated as preventative measures for CIN. Volume expansion via isotonic crystalloid administration (normal saline or isotonic bicarbonate) is recommended with most studies suggesting initiation 1-2 hours before and maintenance for 3–6 hours after contrast exposure. NAC is also recommended at 600-1200 mg orally twice daily, one day before the procedure and on the day of the procedure.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

In 2012, a new definiton for contrast induced nephropathy was put forth by the KDIGO-AKI guidelines. CIN was to be considered a new form of AKI caused by contrast media, and definition criteria for AKI would also apply for CIN now called contrast-induced acute kidney injury (CI-AKI).^[1] However, the most commonly used definition in clinical trails is acute renal insufficiency marked by an increase in baseline serum creatinine of >25% or an absolute increase in serum creatinine of 0.5 mg/dL that occurs 48-72 hours following the exposure to CM.^[2][3] The new definition shifted the 0.5 mg/dL cut-off to 0.3 mg/dL and the 25% increase in baseline to 1.5 times the original serum creatinine.

CIN, defined simply, is acute kidney injury (AKI) that occurs within a time frame after the administration of intravenous contrast agents. According to the 2012 KDIGO AKI guidelines, CIN can be considered as a subtype of AKI related to contrast media, and the term contrast-induced acute kidney injury (CI-AKI) was proposed instead of CIN. The Work Group even advocated the use of the RIFLE/AKIN criteria to define CI-AKI.^[1] A new combined definition was introduced in 2012 to define AKI which included any of the following:

1. Increase in serum creatinine by ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours; or
2. Increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or
3. Urine volume <0.5 ml/kg/h for 6 hours

However, the above definition and cut-offs used have not been thoroughly studied and associated with clinical outcome in CIN specifically. They have been better substantiated in other forms of AKI. Several other definitions have been used in clinical trials. Before 2007, four different definitons were used to define CIN especially post-PCI. Increases in serum creatinine of >0.5 mg/dL, >1.0 mg/dL, and >25% of baseline were used.^[4] The American College of Cardiology National Cardiovascular Data Registry proposed a fourth definition that required a doubling in serum creatinine to a value >2.0mg/dL or the need for dialysis following PCI.^[5] In 2007, Harjai et al showed that only 2 of the four definitions proposed (>0.5 mg/dL increase [P<0.0018] or >25% increase in baseline [P<0.002]) predicted adverse events within the first 6 months following PCI. The authors also proposed a prognostic nephropathy grading system to predict 6 months major adverse cardiovascular events and all-cause mortality. The timing of serum creatinine measurement was 24-48 hours (mean=1.6 days) after the PCI procedure.^[6]

The defined time frame for serum creatinine rise after PCI has also been debated. The PRINCE trial (Prevention of Radiocontrast Induced Nephropathy Clinical Evaluation) showed that the first 24 hours after exposure to CM are the most essential in determining outcome. In 80% of patients with CIN, serum creatinine increase became apparent in the first 24 hours. Virtually all patients with complicated CIN defined as serious renal impairment requiring either acute dialysis or nephrology consultation had a rise in creatinine within that time frame.^[7] However, some patients develop renal impairment after the 24-48 hour time frame. The European Society of Urogenital Radiology guidelines used a cut-off of 72 hours after exposure for the rise in serum creatinine.^[8] It is also important to mention that the peak in serum creatinine can occur up to 5 days after exposure in a minority of patients.^[1]

Following the trend of clinical outcomes after contrast exposure, a more common definition for CIN was recognized that combined 3 criteria:^[2][6]

1. An absolute elevation in serum creatinine of 0.5 mg/dL or and increase of >25% of the baseline creatinine
2. Rise of serum creatinine within 72 hours of exposure to contrast media
3. Exclusion of other diagnoses to explain the renal impairment

To note, recent data have challenged this definition, showing that the traditional rationale requiring >0.5 mg/dL increase in serum creatinine is better predictive of serious adverse events (dialysis and all-cause mortality) when compared to the >25% increase in serum creatinine baseline.^[9]

The use of serum creatinine as a marker of glomerular filtration and kidney injury relies on certain convenience assumptions. Those assumptions include that creatinine is only filtered by the kidney, its excretion rate shows little variability among individuals and over time, and measurement is accurate and reproducible. In fact, none of the previous assumptions are true.^[10] Creatinine is actually filtered and secreted and has been shown to have significant variability with age, sex, ethnicity, and diet.^[11] For that, the trend of following renal function based on previously set reference intervals for the general population has largely been replaced by following changes in serum creatinine or creatinine clearance in an individual compared to their baseline. However, to detect pathological changes in serum creatinine one must first consider the existing variance in measurements related to biological and analytical influences.

Rosano and Brown were among the first to examine intra-individual day-to-day creatinine variability by following two individuals for the period of two months. They showed a combined analytical and biological variability of 0.18 – 0.2 mg/dL with analytical variances accounting for the most significant difference.^[12] The intra-individual variance for creatinine has been discussed in many studies with values ranging from 4.7 to 6.1% in healthy individuals.^[13][14][15] Reinhard et al showed that in patients with pre-existing renal function the variance in serum creatinine can almost reach 8.9%.^[13] The inter-individual variance in creatinine is not as well established, although Reinhard also showed a variance of 14.4% in healthy individuals.^[13] Many laboratory factors can have a noted effect on serum creatinine measurements including calibration which can account for changes of up to 0.23 mg/dL,^[16] unexplained variance among labs (0.07 mg/dl) and unexplained variance with time (0.053 mg/dL).^[17]

It has been suggested that changes in creatinine levels following infusion of contrast media are overestimated especially that people receiving contrast media may have other underlying diseases, might have medical complications or might be treated with medications, which all can possibly alter creatinine levels. In fact, most of the studies about CIN included data about creatinine measurements before and after use of contrast media; however, comparison of the variability of creatinine in these patients receiving IV contrast media have not been always compared to the intra-personal variability in serum creatinine in control groups not receiving contrast media.^[18] Following a medical literature search, 40 articles regarding renal function and contrast media use were found, only 2 of which involved comparing patients receiving contrast media with controls.^[18][19][20] The first article is a prospective controlled study evaluating renal impairment following IV contrast media infusion in 193 patients undergoing brain CT with IV contrast compared to 233 control patients undergoing CT without IV contrast. No significant difference has been noted in the incidence of renal impairment among the two groups (no p-value was provided).^[19] The second article also investigated the difference in incidence of renal impairment among 3188 patients receiving a CT scan either with or without contrast media and reported no significant difference in the incidences of renal impairment among patients undergoing a CT scan with or without contrast media.^[20]

Based on the hypothesis that changes in creatinine levels following contrast media are overestimated, Newhouse et al investigated the variations (increase or/and decrease) in creatinine levels within five days among 32,161 patients not receiving contrast media. Data has been generated from electronic medical records of 32,161 patients who underwent serial creatinine levels over five consecutive days. These patients had either normal or abnormal creatinine baseline measurements, possible underlying conditions or/and possible medications intake. While more than 50% of the patients had a cumulative creatinine change of at least 25% over the course of five days, more than two fifth of the patients had a cumulative creatinine change of 0.4 mg/dl.^[21]

KDIGO Clinical Practice Guideline for Acute Kidney Injury^[22]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

Most of data related to the contrast nephropathy come from animal models. Studies show evidence of acute tubular necrosis (ATN) but the mechanism by which ATN occurs is not well understood.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

The pathophysiology of CIN is not clearly understood; however, several attempts have been made to explain the underlying mechanism. It is generally agreed that CIN is due to a combination of several influences brought on by contrast-media infusion rather than a single process. The most important mechanism thought to be involved in CIN is a reduction in renal perfusion and subsequent hypoxia. This has been attributed to several alterations in the renal microenvironment including activation of the tubuloglomerular feeback, local vasoactive metabolites including adenosine, prostaglandin, NO, and endothelin as well as increased interstitial pressure.^[1] Although sometimes considered controversial, studies have also proposed injury to renal tubular cells as another contributor both via a direct cytotoxic effect and via reactive oxygen species production.^[2]

Several mechanisms have been put forth to explain the development of nephropathy following contrast administration. Broadly, the pathophysiology can be divided into renal vascular compromise and cytotoxic tubular cell injury.

The renal vascular bed is supplied by small capillaries known as the vasa recta. While these small vessels have a diameter similar to that of other capillaries, their length is usually several times longer, creating higher vascular resistance. To offset that, viscosity needs to be maintained at its lowest demonstrated in Poiseuille’s law:

Several rat models have shown association between plasma viscosity, increased vascular resistance, and contrast-media infusion. As viscosity increases, resistance in the vasa recta can rise to cause significant renal tissue hypoperfusion^[2] Some agents have an inherently higher viscosity leading to higher resistance while others can interact with red blood cells causing a decrease in deformability and a secondary increase in resistance.^[3]

Increased viscosity also transfers to tubular fluid which is usually low in proteins and less viscous than plasma. Some models have shown that as urine concentration occurs in the tubules, viscosity increases significantly in the renal tubules leading to an increase in renal interstitial pressure.^[4][5] The rising pressure further increases vasa recta hypoperfusion and also contributing to hypoxia.

The tubuloglomerular feedback (TGF) describes the function of the macula densa, a dense collection of specialized epithelial cells at the junction of the thick ascending loop and the distal convoluted tubule. The macula densa senses sodium delivery to the distal tubules via a Na⁺/K⁺/2Cl^– transporter. High sodium delivery is perceived as high glomerular filtration which causes adenosine release from the macula densa and vasoconstriction of the afferent arteriole to decrease filtration.^[6] The osmotic diuresis theory hypothesizes that contrast media cause increased natriuresis and thus activate TGF leading to vasoconstriction. This theory has been challenged multiple times and studies have shown little or no effect of the TGF on CIN. Tangibly, the use of furosemide, a Na⁺/K⁺/2Cl^– transporter blocker, was not shown to significantly prevent CIN after cardiac angiography.^[7]

Initial animal studies showed that contrast media infusion causes a biphasic vascular response. With early infusion, a short phase of renal vasodilation arises followed by a prolonged phase of vasoconstriction eventually leading to tissue hypoxia.^[8] Several studies have tried to explain the mechanism underlying the vasoconstrictive phase with common emphasis on an imbalance of vasoactive substances brought on by the contrast media.

Adenosine

Adenosine is a byproduct of ATP metabolism responsible for certain alterations in renal hemodynamics. It’s most important role is in the tubuloglomerular feedback (TGF) but has other functions dependening on receptor subtype.^[9] The renal vasculature has 2 main classes of adenosine receptors: A₁ and A₂. The A₁ receptor is found in high concentrations in the afferent arteriole and glomerular mesangium mediating vasoconstriction and mesangial contraction respectively. The A₂ receptor is more widely distributed and mediates vasodilation usually enhancing renal medullary blood flow.^[10] Adenosine has been proposed as a mediator of vasoconstriction following contrast infusion but a number of studies have shown that it’s role may be overestimated in CIN. It was shown that in renal insufficiency models adenosine may play role in hypoperfusion. This may be attributed to the baseline requirements of the diseased kidney and that activation of the A₁ receptors may be detrimental to renal function.^[11] However, blocking A₁ receptors in rats prior to contrast injection did not appear to decrease medullary hypoperfusion.^[12] It was also shown that the decrease in GFR and overall reduction in renal plasma flow cannot be attributed to adenosine activity alone.^[13]

Endothelin

Endothelin is a peptide released from endothelial cells mediating vasoconstriction or vasodilation depending on the vascular bed and the receptors in question. Broadly ET-A receptors mediate vasoconstriction while ET-B receptors mediate vasodilation. It has been postulated that an endothelin response to contrast media is responsible for CIN. Several studies have also shown increased endothelin levels in the urine and plasma after contrast exposure.^[14] However, Wang et al showed that blocking both ET-A and ET-B receptors in people before exposure to contrast media increased the risk of CIN.^[15] This may be in part correlated to the blunting of the effect of ET-B responsible for vasodilation as well as the inhibition of the negative feedback loop initiated by ET-B that decreases endothelin secretion.^[16] Investigation into a selective ET-A receptor antagonist is underway, with initial animal studies showing some promise.^[17]

Renal cortical perfusion is usually very high. However, the renal medulla, particularly the deeper potion of the outer medulla, is maintained at very low PO₂levels that can reach 20 mm Hg. This area is relatively distant from the vasa recta often being the first to be damaged in hypoxic injury.^[18] Although contrast media induce medullary hypoperfusion possibly via vasoconstriction, they also and increased work-load for tubular cells exacerbating the already existing hypoxic conditions by increasing oxygen consumption.^[2]

Contrast media have been implicated in direct and indirect cytotoxic effects on renal tubular cells.

Previously regarded as the main mechanism of renal injury, osmotic stress was not substantiated as a strong component especially when contrast media were compared to other substances with high osmolarity namely mannitol.^[19] Still, although the proposed mechanism for the osmotic theory could not be verified, osmolarity of the contrast medium has been clinically linked to differences in outcome. Initially, small scale studies showed no difference between high-osmolar and low-osmolar contrast media.^[20] However, in 1995, a prospective randomized trial by Rudnick et al revealed that patients with renal insufficiency and diabetes mellitus had a significantly lower risk of CIN with low-osmolar media.^[21] With the introduction of iso-osmolar media, several comparative studies most importantly the NEPHRIC trial by Aspelin et al showed that iso-osmolar media is highly superior in high risk patients with pre-existing renal disease and diabetes. The trial demonstrated that the incidence of CIN in the iso-osmolar contrast group was 3.1% compared with 26.2% in the low-osmolar contrast group.^[22] Results of the NEPHRIC trial have sometimes been questioned to the lack of reproducibility in other trials. However, it is generally agreed that iso-osmolar contrast media pose the lowest risk of CIN among other contrast agents. Despite those findings, the underlying mechanism linking osmolarity to CIN is still poorly understood.

Reactive oxygen species (ROS) are normally produced in baseline conditions but increase drastically during oxidative stress. The most commonly produced ROS species are hydroxy radical (OH^–), hydrogen peroxide (H₂O₂), and superoxide anion (O₂^–).^[23] In models investigating diabetic nephropathy, excessive ROS were associated with a decrease in NO and subsequent blunting of vasodilation leading to renal hypoperfusion.^[24] Similarly for CIN, human and animal experiments that tried reducing the hypothesized ROS load caused by contrast media have shown attenuated reductions in GFR and a lower risk of CIN.^[25][26] This underlines the interest in targeting ROS as a treatment for CIN with several antioxidants already investigated in the treatment of CIN.

The administration of gadolinium-based contrast media among patients with chronic kidney disease (CKD) has long been considered safe as compared to iodinated contrast media. Nevertheless, reports about the renal toxicity of gadolinium describe mixed results. While earlier articles report the safety of gadolinium-based contrast media,^{[27][28][29][30][31][32][33][34]} others demonstrate that gadolinium-based contrast media is not as safe as it is thought among patients with CKD.^{[35][36][37][38]} This discrepancy in results might be explained by the lack of randomization, the different dosages of gadolinium that was administered, and the small number of patients in most of the studies.

In a study of 25 patients with CKD (GFR ≤40 mL/min.1.73m²), 28 % of the patients developed CIN (defined as increase in serum creatinine by > 0.5 mg/dL within 48 hours) following the administration of gadolinium-based contrast media compared to 6.5% in those who received iodinated contrast media.^[35] In another retrospective study of 91 patients with GFR ranging from 15 to 59 mL/min.1.73m², the administration of 0.2 ml/kg of gadolinium based contrast lead to CIN in 12.1% of patients.^[36] Another study reports that out of 195 CKD patients who received gadolinium, nephrotoxicity occurred in 3.5% of the patients among whom creatinine clearance ranged from 9 to 61 mL/min.1.73m².^[39] In addition, 5 out of 10 patients with a GRF <50 mL/min.1.73m² (mean GFR of 32 mL/min.1.73m²) in another study developed gadolinium associated nephrotoxicity.^[38]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

The differential diagnosis includes atheroembolic renal failure, acute renal failure, acute interstitial nephritis, and acute tubular necrosis.

• Acute tubular necrosis:a medical condition involving the death of tubular cells that form the tubule and transports urine to the ureters. the occurrence of Ischemia can be from endogenous toxins, such as free hemoglobin or myoglobin, or from exogenous toxins, such as antibiotics, chemotherapeutic agents, and heavy metals

• Atheroembolic renal failure: which usually occur after 7 days of contrast exposure with a prolonged course. Manifestation of thromboembolism include blue toes and Livedoid vasculitis,which is due to embolism induced obstruction of capillaries. Transient eosinophilia have been associated with thromboembolism.

• Acute renal failure: causes are numerous and include low blood volume from any cause, exposure to substances harmful to the kidney, and obstruction of the urinary tract. AKI is diagnosed on the basis of characteristic laboratory findings, such as elevated blood urea nitrogen and creatinine, or inability of the kidneys to produce sufficient amounts of urine. acute renal failure is usually oliguric, and recovery occur in 2-3 weeks.

• Acute interstitial nephritis: this disease can be either acute or chronic. Chronic cases eventually ending in kidney failure. Manifestations include fever, skin rash, eosinophilia, and eosinophiluria.

• Acute tubular necrosis– a medical condition involving the death of tubular cells that form the tubule and transports urine to the ureters. the occurrence of Ischemia can be from endogenous toxins, such as free hemoglobin or myoglobin, and light chains, or from exogenous toxins, such as antibiotics, chemotherapeutic agents, organic solvents, and heavy metals

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

Incidence of CIN in the general population have been reported to be 0.6–2.3%.^[1] It is considered to be the third most common cause of renal failure with an overall mortality rate of 19.4%^[2] The incidence of CIN among patients undergoing PCI is approximately 7%.^[3]

Although many regulations and precautions have been followed in the care of hospitalized patients, renal function deterioration remains a common event, the rate of nephropathy following exposure to CM, used in diagnostic and interventional studies differs according to the definition used, and also depend on other variables such as the type of radiology procedure performed, the dose and type of contrast agent administered. Incidence found to be 14.5% in a large epidemiological study^[4], in other studies which define CIN as > 25% increase in serum creatinine levels over baseline in the first 5 days, Rates may vary according to the presence of risk factors. Patients with diabetes has been reported to be 9–40% in patients with mild-to-moderate chronic renal insufficiency, and 50–90% in those with severe chronic renal insufficiency.^{[5] [6]} An overall incidence of CIN in the general population is reported to be 0.6–2.3%.^[1] The overall mortality rate was 19.4% and was similar among patients for all causes of renal insufficiency, except sepsis.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]

Many factors have been associated with an increased risk of nephropathy in patients exposed to contrast media. Pre-existing renal insufficiency, pre-existing diabetes, age, volume of CM, and reduced intravascular volume are examples for these risk factor.^[1][2] The total risk rises as the number of risk factors increase, it has been recommended that every known risk factor should be analyzed, to properly evaluate a total cumulative risk of developing contrast-induced nephropathy. A clinical prediction rule is available to estimate probability of nephropathy (increase ≥25% and/or ≥0.5 mg/dl in serum creatinine at 48 h)^[3]

A systematic review has quantified the ability of clinical prediction rules to predict contrast-induced nephropathy.^[4]

Studies have shown that it ts the most critical risk factor, particularly if associated with elevated level of serum creatinine, with a reported high incidence ranging from 14.8 to 55%^{[5] [1] [6]} Pre-procedure hydration and the use of non-ionic CM could not prevent the occurrence of CIN in one-third of 439 consecutive patients who underwent PCI .^[6]

Although baseline creatinine is not reliable enough for identification of patients at risk for CIN, this is because serum creatinine value varies with age, muscle mass, and gender, one of the studies shown that the higher the baseline creatinine value, the greater is the risk of CIN.

Baseline plasma creatinine level is less than or equal to 1.2 mg/dl, the risk of CIN is only 2%

Values of creatinine in the range of 1.4–1.9 mg/dl, the risk of CIN compared with that in the previous group increases fivefold (10.4%)

Patients with baseline creatinine level more than 2.0 mg/dl, more than half of them (62%) subsequently develop CIN.^[7]

Due to complications caused by diabetes, especially cardiovascular diseases that require radiological procedures and exposure to CM, and the fact that Diabetes mellitus has a wide prevalence in general population, diabetic patients represent a significant proportion of those undergoing contrast exposure with incidence of CIN varies from 5.7 to 29.4%.^[8][9]

Diabetes mellitus with associated renal insufficiency has been identified as an independent risk factor for contrast nephropathy, with as many as 56% of those who develop the condition progressing to irreversible renal failure. In addition, diabetic patients who have advanced chronic renal failure (serum creatinine levels > 3.5 mg/dL) due to causes other than diabetic nephropathy are significantly at higher risk of developing CIN.^[10]

Elderly have a higher risk to develop CIN compared to other population, the reasons of this elevated risk were not studied specifically, authors suggested that it is probably multifactorial. Theories explain this elevated risk by age-related changes in renal function, diminished glomerular filtration rate, tubular secretion, and concentrating ability. Several studies proved that older age is an independent predictor of CIN.^{[11] [12]}

The association between the amount of CM and the risk of CIN development has been proved,^{[1][12][13][14][15][16]} The higher volume of CM, the greater the damaging effect in the presence of other risk factors, even a low dose of CM can induce permanent renal failure and the need for dialysis in patients with chronic kidney disease.

Exposure to contrast media through different procedures within 72 hours increase the risk of the patient’s developing CIN.^[17][18][19]

Clinical studies indicated that the use of low osmolarity CM reduces the risk of nephropathy in high-risk patients compared with the use of High osmolarity CM.^[20][21]

The suggested mechanism is through renal ischemia, there is a steadily increased rates of CIN as pre-procedure hematocrit decreased.^[22] While decrease the effective blood volume lead to decrease the renal perfusion, thus enhance the ischemic effect of the CM.^{[23][24][25][18]}

Some drugs have been reported to render the kidney more vulnerable to the nephrotoxic effect of the contrast, directly nephrotoxic drugs (e.g., cyclosporin A, aminoglycosides, amphotericin, and cisplatin) and those that inhibit the local vasodilatory effects of prostaglandins (e.g., nonsteroidal antiinflammatory drugs NSAIDs)^[26]

Sepsis has been reported as being a risk factor through direct damage of the renal tubules by bacterial toxins. Hypertension, multiple myeloma, peripheral vascular disease, and atopic allergy also have been reported as risk factors.^{[27] [17]}

KDIGO Clinical Practice Guideline for Acute Kidney Injury^[28]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

CIN is often characterized by a transient increase in serum creatinine that peaks at 3 to 6 days after exposure to radiocontrast. Rarely, CIN leads to ESRD in patients with baseline kidney disease. CIN is also associated with increased risk for adverse cardiovascular events and a higher all-cause mortality. Prognosis is especially poor in patients that require hemodialysis after CIN.

Usually, CIN causes a form of transient acute kidney injury with bridging hemodialysis only needed in a few cases until renal function returns to normal. Serum creatinine usually peaks between 3 to 6 days following contrast exposure and slowly decreases afterwards.^[1] The most important determinant of the peak serum creatinine and the creatinine trajectory is the baseline creatinine clearance.

The association between early creatinine rise following contrast administration and the occurrence of CIN is not very clear, particularly regarding the cut off value of the variation of the serum creatinine from baseline as well as the time frame of the variation. It has been demonstrated that the change in serum creatinine between baseline and 12 hours after the administration of the contrast media is the best predictor of CIN.^[2] The sensitivity and specificity of the change in serum creatinine for the subsequent occurrence of CIN are 75% and 72% respectively for a creatinine change of > 5%,^[2] and 43% and 93% for a creatinine change of > 15%.^[3] The PRINCE trial (Prevention of Radiocontrast Induced Nephropathy Clinical Evaluation) demonstrated that the first 24 hours after exposure to contrast media are the most essential in determining renal failure outcome. In 80% of patients with CIN, serum creatinine increase became apparent in the first 24 hours. Virtually all patients with complicated CIN defined as serious renal impairment requiring either acute dialysis or nephrology consultation had a rise in creatinine within that time frame.^[4] However, according to other studies, a minority of patients develop renal impairment after the 24-72 hour time frame taking up to 5 days after exposure.^[5]

Studies have substantiated greater all-cause and cardiovascular mortality,^[6] prolonged duration of hospitalization,^[7] and late cardiovascular events^[8] associated with CIN. The evidence is seen mostly in patients undergoing PCI.^[9][10] Weisbord et al showed that an absolute increase in serum creatinine of 0.25 to 0.5 mg/dL within 72 hours after coronary angiography was associated with significantly greater odds for in-hospital mortality in the 30 day period following the procedure.^[10] The need for dialysis following CIN is also a separate prognostic indicator. Dialysis requirement has been associated with a fivefold increase in all-cause mortality when compared to patients with CIN not requiring renal replacement. Furthermore, mortality in the former group was as high as 81% at 2 years.^[11] Several of the studies targeting prognosis following CIN have been limited by the confounding factors mostly because high risk patients for CIN are naturally at higher risk for cardiovascular complications.

Harjai et al proposed a nephropathy grading system in 2008 to predict prognosis in patients with CIN after PCI. The classification system included 3 separate nephropathy grades:

• Grade 0 = no nephropathy (increase in Cr<25% and <0.5mg/dl)
• Grade 1 = mild nephropathy (increase in Cr>25% but <0.5mg/dl)
• Grade 2 = significant nephropathy (increase in Cr>25% and >0.5mg/dl)

They compared the classification system to the incidence of major adverse cardiovascular events (MACE) after 6 months. The grading system showed significant correlation with adverse outcomes (G0=12.4% / G1=19.4% / G2=28.6% [P= 0.003]) and all-cause mortality (G0=10.2% / G1=10.45% / G2=40.9%, [P<0.0001]).^[12]

Shown below is a table summarizing the suggested classification system, incidence of MACE after 6 months and all-cause mortality.

End stage renal disease requiring chronic dialysis following CIN occurs in a small proportion of patients^[13], although data is still scarce. Usually patients that require chronic dialysis have some form of advanced kidney disease prior to exposure to contrast media.

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