The pharmacist’s role in the prevention of contrast-induced nephropathy

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Low osmolar or iso-osmolar contrast agents, hydration with saline and avoidance of nephrotoxic drugs are key measures in preventing acute kidney injury

Caroline Ashley
MSc BPharm MRPharmS

Lead Specialist
Pharmacist Renal
Services

Royal Free Hospital,
London

Contrast-induced nephropathy (CIN) is a well recognised cause of hospital-acquired renal failure. The estimated overall incidence of CIN is 1-2% but in high-risk groups, such as those with diabetes mellitus and pre-existing renal impairment, the risk of developing CIN may be as high as 50%. Adverse outcomes of CIN include the need for renal replacement therapy, lengthened hospital stay, major cardiac adverse events and increased mortality. Increasing numbers of diagnostic and therapeutic procedures requiring the use of intravenous contrast media are being performed, often in elderly patients and those with significant co-morbidities.

Once contrast-induced acute kidney injury develops, there is no specific treatment and management is  the same as for any cause of acute kidney injury, with a focus on maintaining fluid and electrolyte balance. The best treatment, therefore, is prevention.

It is important to be aware of the risk factors that contribute to CIN and the steps that can be taken to prevent it.

Definition of CIN

CIN is usually defined as either an absolute increase in serum creatinine of 44 micromol/L (0.5 mg/dl) or a 25% increase from the baseline value 48 hours after intravascular injection of contrast media

Mechanism
After contrast is injected, renal blood flow transiently increases and then decreases over a longer period, suggesting that renal ischaemia is a major factor in the pathogenesis of CIN. Contrast agents reduce oxygen tension in both the cortex and the medulla.

This effect may be caused by osmotic diuresis from hyperosmolar agents and the release of vasoconstrictive compounds, such as endothelin, prompting an increase in the work of active transport mechanism. Blockade of vasodilatory compounds, such as nitrous oxide and prostaglandins, also appears to exacerbate markedly contrast-induced medullary hypoxic injury.

Several clinical and experimental observations suggest that the hyperosmolality of contrast media may also play a role in the pathogenesis of CIN. According to current theories, hyperosmolality activates tubuloglomerular feedback and/or causes an increase in tubular hydrostatic pressures, either of which could lead to a decrease in glomerular filtration. Osmotic diuresis, produced by contrast media, may result in increased active transport of sodium in the thick ascending limb and also in vasoconstriction; both of these responses could lead to worsened medullary hypoxaemia.

Apoptotic cell death is one of the direct effects on renal endothelial cells of reactive oxygen species, formed as a result of post-ischaemic oxidative stress, that can lead to acute renal failure.

Risk factors for CIN
Factors associated with the development of CIN include:
* pre-existing renal impairment
* diabetes mellitus
* advanced age
* peri-procedural intravascular depletion
* congestive heart failure
* volume and type of contrast administered
* concomitant use of other nephrotoxic drugs
Low haematocrit, which could contribute to renal hypoxia, has also been implicated

Types of radiocontrast agents
The osmolality of blood, and of the cerebrospinal fluid, which surrounds the brain and spinal cord, is about 290 mOsmol/kg. Almost all of the currently available contrast media have osmolalities in excess of this figure, though some are very much higher than others.

Iodinated radiocontrast agents are either ionic or non-ionic and of variable osmolality:

• First generation agents are ionic monomers; they are highly hyperosmolar (approximately 1400 to 1800 mOsmol/kg) compared to the osmolaliy of plasma.
• Second generation agents, such as iohexol, are non-ionic monomers with a lower osmolality than the first generation contrast media; however, they still have an increased osmolality (500 to 800 mOsmol/kg) compared with plasma. In addition, there is now an ionic low osmolar contrast agent, ioxaglate.
• The newest non-ionic contrast agents are iso-osmolar, being dimers with an osmolality of
  approximately 290 mOsmol/kg (iodixanol is the first
  such agent).

A decreased incidence of CIN appears to be associated low or iso-osmolar. In practice, hyperosmolar ionic monomer agents are no longer used intravenously.

A randomised trial involving almost 1200 patients undergoing coronary angiography compared the low osmolar non-ionic agent iohexol with the high osmolar agent diatrizoate.[1] The use of iohexol was associated with less nephrotoxicity in patients with renal insufficiency alone or with concomitant diabetes mellitus. Among patients with a baseline serum creatinine above 123 micromol/L, a rise in the serum creatinine of at least 88 micromol/L was seen less frequently after the use of iohexol than with the ionic agent (7.2% versus 15.8%). The difference was greater in patients with diabetes (11.8% versus 27%).

Non-ionic iso-osmolar agents
The use of non-ionic iso-osmolar agents (approximately 290 mOsmol/kg) may be associated with a lower risk of nephropathy than low osmolar agents, particularly amongst patients with diabetes and renal insufficiency. A meta-analysis of 16 double-blind, controlled trials including 2727 participants compared the rates of CIN with iodixanol (iso-osmolar) with low-osmolar contrast agents.2 Among the 502 patients with chronic kidney disease (CKD), defined by serum creatinine >133 micromol/L and/or an estimated creatinine clearance <60 ml/min, the rate was 2.8% versus 8.4% with a low-osmolar agent. The benefit was greater among the 231 patients with both CKD and diabetes — 3.5% versus 15.5%. The authors concluded that use of the iso-osmolar iodixanol was associated with smaller rises in creatinine and lower rates of CIN than low-osmolar contrast media, especially in patients with CKD or CKD + diabetes. However, some concerns have been raised over the methodological quality of this study and there remains some uncertainty about the precise roles of low-osmolar and iso- osmolar contrast media in patients with and without pre- existing CKD and diabetes.

Hydration
The most effective measure to prevent contrastinduced nephropathy is to ensure that the patient is well-hydrated. However, whether isotonic (0.9%) saline, half-isotonic (0.45%) saline or isotonic (1.26%) sodium bicarbonate is the optimal hydration solution to use is unclear.

Intravenous saline
In a prospective randomised trial, 1620 patients were treated with either 0.9% or 0.45% saline at a rate of 1 ml/kg/hour starting the morning of the procedure and continuing until the next morning.[3] Baseline serum creatinine was the same in both groups. The overall incidence of CIN was 1.4% and was significantly lower in patients given 0.9% saline (0.7% versus 2.0%). The benefit of isotonic saline was more pronounced in patients with diabetes (0% versus 5.5%) and those given more than 250 ml of contrast (0% versus 3%). However, there was no difference in those with significant renal dysfunction (serum creatinine >141 micromol/L).

Intravenous bicarbonate
Since alkalinisation may protect against free radical injury, the possibility that sodium bicarbonate may be superior to isotonic saline has been investigated in several trials. In a prospective trial 119 patients with and without renal insufficiency were randomised to receive either isotonic saline or bicarbonate- as a bolus of 3 ml/kg/hour for one hour prior to contrast followed by  a 1 ml/kg/hour infusion for six hours afterwards.[4] Baseline serum creatinine levels were similar (mean values — 151 micromol/L for the saline group and 167 micromol/ L for the bicarbonate group). The primary outcome (>25% increase in serum creatinine within 2 days) was achieved in 1.7% of the sodium bicarbonate group and 13.6% of the comparator (isotonic saline) group.

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In contrast, other trials have shown no benefit with isotonic sodium bicarbonate compared to isotonic sodium chloride. One trial included 353 patients who underwent coronary angioplasty.[5] All participants had an estimated glomerular filtration rate of <60 ml/min, and either a history of diabetes, heart failure, hypertension or were aged above 75 years. Patients received either isotonic saline or bicarbonate at a rate of 3 mL/ kg/hour for one hour prior to and then 1.5 mL/kg/hour during and for four hours after the procedure. There was no difference between groups in the primary outcome (25% decrease in estimated glomerular filtration rate on days 1-4 following the procedure).

Oral hydration
Several small trials have evaluated the effectiveness of oral hydration or salt loading in preventing CIN. One trial that included only unrestricted oral fluids (ie, no salt) found a much higher rate of acute kidney injury after contrast than those given isotonic saline.[6] In this trial, 53 patients were randomly assigned to either unrestricted oral fluids or to intravenous normal saline at 1 mL/kg/hour for 24 hours beginning 12 hours prior to the procedure. Acute renal failure was significantly more frequent with oral hydration (35% versus 4%).

Acetylcysteine
Acetylcysteine is a thiol compound with antioxidant and vasodilatory properties. Although not well understood, it is presumed to exert its beneficial effects in contrast-induced nephropathy by minimising both vasoconstriction and generation of oxygen free radicals after radiocontrast agent administration. Numerous prospective trials examining the prophylactic effect of acetylcysteine have been performed with conflicting results. Therefore, the overall prophylactic efficacy of acetylcysteine has been assessed in multiple metaanalyses. Several have suggested a substantial benefit, reporting risk reductions of up to 50%, whereas others have reported less substantial, and occasionally nonsignificant differences.

The most commonly studied dose is 600 mg orally twice daily for two days. However, a study comparing 600 mg and 1200 mg twice daily suggested slightly better outcomes with the higher dose.[7]

Acetylcysteine may also be given intravenously. In a trial of 80 patients with a mean baseline creatinine of 160 micromol/L, acetylcysteine (150 mg/kg prior to the procedure followed by 50 mg/kg for 4 hours after the procedure) was compared with isotonic saline (1 mL/kg/hour for 12 hours pre- and post-contrast).[8] Fewer patients in the acetylcysteine group (5% versus 20%) developed acute renal failure. However, seven patients developed anaphylactoid reactions.

REMEDIAL trial
The REMEDIAL trial randomly compared three alternative preventive strategies-sodium bicarbonate infusion plus acetylcysteine, sodium chloride 0.9% plus acetylcysteine, or isotonic saline plus acetylcysteine and ascorbic acid.[9] A total of 326 patients with a serum creatinine >177 micromol/L or a granular filtration rate <40 ml/min/1.73m2 were included; almost half the enrolled patients had diabetes. All patients received iodixanol, an iso-osmolar, non-ionic contrast agent. A
significantly lower incidence of the primary endpoint (>25% increase in serum creatinine within 2 days of contrast) was observed in patients given sodium bicarbonate plus acetylcysteine (1.9% versus 9.9% and 10.3% in the other two groups).

Other measures
Furosemide, mannitol and low-dose dopamine have all been used as measures to avoid CIN. One study evaluated 50 patients (24 of whom had diabetes) with chronic kidney impairment (mean serum creatinine 220 micromol/L) who were about to undergo coronary angiography.[10]The patients were randomly assigned to receive saline, dopamine (2 micrograms/kg/min), or mannitol (15% given at 100 mL/hr). Saline hydration was associated with a 40% incidence of renal dysfunction(a rise in the serum creatinine of 25%) in both patients with and without diabetes. However, the dopamine and mannitol groups showed a 75-83% incidence of renal dysfunction in subjects with diabetes. A similar study using 0.45% saline plus intravenous furosemide 80 mg given 30 minutes before the procedure showed a similar increased risk of developing CIN.[11]

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There are a few reports suggesting that theophylline, an adenosine antagonist, can prevent CIN. One study randomised 39 patients undergoing scans with contrast media to receive either intravenous theophylline or placebo.[12] Although no patient in either group developed CIN, 4 hours after contrast administration the granular filtration rate decreased in the placebo group from 88 mL/min at baseline to 75 mL/min; it remained unchanged in the theophylline group. However, several other placebo-controlled studies using theophylline (given orally or intravenously) showed no episodes of CIN, but all the studies were in low-risk patients. In addition, theophylline has potential risks, including ventricular arrhythmias, seizures, and shock” all of which may be potentiated by a variety of other drugs.[13]

Haemodialysis and haemofiltration
Numerous studies have demonstrated that 2-3 hours of haemodialysis effectively removes 60% to 90% of contrast medium.[14] Several studies have explored the use of haemodialysis in high-risk patients, but most have failed to demonstrate a reduced incidence of CIN.

However, another study found that haemofiltration significantly reduced CIN in patients at high risk.[15] Patients with CKD undergoing coronary angiography were randomised to undergo either haemofiltration in an intensive care unit or parenteral saline hydration. Haemofiltration was started 4-6 hours before contrast administration, stopped for the procedure, then resumed for an additional 18 to 24 hours. Isotonic saline was used as replacement fluid, given at a rate of 1 L /hour, which matched the ultrafiltration rate, so that the patient experienced no net fluid loss. In the control group, isotonic saline was given at 1 mL/kg/hour for 6-8 hours before and 24 hours after angiography.

The incidence of CIN was 5% in the haemofiltration group compared with 50% in the control group. However, given the logistical effort and high cost associated with haemofiltration, larger randomised trials should be performed before this technique can be recommended as standard prophylaxis against CIN in highrisk patients.

Drug-contrast interactions
Directly nephrotoxic drugs (eg, ciclosporin, aminoglycosides, amphotericin, and cisplatin) and those that inhibit the local vasodilatory effects of prostaglandins (eg, nonsteroidal anti inflammatory drugs (NSAIDs)) can potentiate CIN. Where possible such drugs should be discontinued before the procedure. This may not be an option for aminoglycosides and close monitoring of plasma levels is recommended in such cases.

Drugs that are cleared by the kidneys, such as digoxin, may also be affected. Close monitoring of renal function, with drug level monitoring and possible dose adjustment, may be warranted.

Metformin is not a risk factor for developing CIN but lactic acidosis is a rare complication of metformin treatment. Patients who develop CIN while taking metformin may be at higher risk of developing lactic acidosis. For this reason, metformin should be discontinued in patients undergoing contrast studies. The current SPC for Glucophage (metformin) recommends that it should be discontinued, prior to or at the time of the test, and not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal. It is normal practice at the Royal Free Hospital for radiographers to ask patients if they are taking metformin before starting the test.

The Contrast Media Safety Committee of the European Society of Urogenital Radiology has produced a summary document on interactions between contrast media and other drugs.[16]

CIN is associated with an increased risk of morbidity and mortality and there is no treatment for the conditionother than supportive measures. It is therefore important to minimise the chances of its occurrence wherever possible. Pharmacists need to understand the risk factors for CIN and the steps that can be taken to prevent it so that they can contribute effectively to this aspect of medicines’ usage.

References

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Hewett JA. Randomised prospective trial to assess the role of saline hydration on the development of contrast nephrotoxicity.
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13. Pflueger A, Larson TS, Nath KA, King BF, Gross JM, Knox FG. Role of adenosine in contrast media-induced acute renal failure in diabetes mellitus. Mayo Clin Proc 2000;75:1275—1283.
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