Post-contrast acute kidney injury. Part 2: risk stratification, role of hydration and other prophylactic measures, patients taking metformin and chronic dialysis patients
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The Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) has updated its 2011 guidelines on the prevention of post-contrast acute kidney injury (PC-AKI). The results of the literature review and the recommendations based on it, which were used to prepare the new guidelines, are presented in two papers.
Areas covered in part 2
Topics reviewed include stratification of PC-AKI risk, the need to withdraw nephrotoxic medication, PC-AKI prophylaxis with hydration or drugs, the use of metformin in diabetic patients receiving contrast medium and the need to alter dialysis schedules in patients receiving contrast medium.
• In CKD, hydration reduces the PC-AKI risk
• Intravenous normal saline and intravenous sodium bicarbonate provide equally effective prophylaxis
• No drugs have been consistently shown to reduce the risk of PC-AKI
• Stop metformin from the time of contrast medium administration if eGFR < 30 ml/min/1.73 m 2
• Dialysis schedules need not change when intravascular contrast medium is given
KeywordsContrast media Acute kidney injury Metformin Haemodialysis Practice guidelines
Abbreviations and acronyms
Angiotensin Converting Enzyme Inhibitor
American College of Radiology
Appraisal of Guidelines for Research and Evaluation
Agency for Healthcare Research and Quality
Acute Kidney Injury
Angiotensin-II Receptor Blocker
Contrast-Induced Acute Kidney Injury
Chronic Kidney Disease
Contrast Media Safety Committee
Computed Tomography Pulmonary Angiography
Dextrose 5% in Water
Estimated Glomerular Filtration Rate
European Society of Urogenital Radiology
Federal Drugs Administration
Glomerular Filtration Rate
Non-Steroidal Anti-Inflammatory Drug
New York Heart Association
Oxford Centre for Evidence Based Medicine
Post-Contrast Acute Kidney Injury
Percutaneous Coronary Intervention
Radiological Society of the Netherlands
Randomised Controlled Trial
Renal Replacement Therapy
The Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) produced their most recent guidelines on what was then termed contrast-induced nephropathy (CIN) in 2011 . Guidelines on the use of contrast media (CM) in patients on dialysis and on the use of CM in diabetic patients using metformin were published in 2002 and 2014 [2, 3]. This review provides recommendations for updating the CMSC guidelines which were obtained using a structured literature review based on clinical questions and Patient–Intervention–Comparator–Outcome (PICO) formatting. Since the literature related to the topics considered is so large, the results of the review have been split into two papers. The review only considers post-contrast kidney injury (PC-AKI) after iodine-based CM because acute kidney injury is not associated with gadolinium-based contrast agents in doses approved for clinical magnetic resonance imaging.
The role of questionnaires and risk scores to identify at-risk patients with reduced renal function
The need to stop nephrotoxic medication before giving CM
The optimal hydration protocols for protecting against PC-AKI
The possible role of prophylactic drug treatment in preventing PC-AKI
The need to adapt metformin administration when giving CM
The need to alter schedules for dialysis in the period before and after CM administration
Recommendations are made for items 1–6. The recommendations have been incorporated into version 10 of the ESUR CMSC guidelines, at the end of this paper (Table 4).
Materials and methods
The recommendations were prepared using the Appraisal of Guidelines for Research and Evaluation (AGREE) II document . A guideline Writing Group (WG) prepared ten clinical questions in PICO format . Systematic search strings were developed with a professional librarian for four different biomedical literature databases (PubMed, Web of Science, Embase and the Cochrane Library). The titles and abstracts were screened for relevance and selected on predefined inclusion and exclusion criteria. Emphasis was put on comparative studies with strong scientific evidence, such as meta-analyses and systematic reviews, and prospective randomised controlled trials (RCTs). The six systematic searches in this manuscript yielded 3402 references of which 445 were selected on the basis of title and abstract. After review of the full text of these 445 publications, 145 were selected for inclusion in this paper. The quality of the evidence from the selected articles was evaluated according to the Oxford Centre for Evidence Based Medicine levels of evidence: grade A, established scientific evidence; grade B, scientific presumption; grade C, low level of evidence . When there was no scientific evidence, recommendations were based on WG consensus and were graded as expert opinion (grade D).
The full description of the materials and methods appears in part 1.
The term intra-arterial injection with first pass renal exposure indicates that contrast medium reaches the kidneys in a relatively undiluted form, e.g. injection into the left heart, thoracic and suprarenal abdominal aorta or the renal arteries. The term intra-arterial injection with second pass renal exposure indicates that contrast medium reaches the renal arteries after dilution either in the pulmonary or peripheral circulation, e.g. injection into the right heart, pulmonary artery, carotid, subclavian, coronary, mesenteric or infrarenal arteries.
Question 5: Should questionnaires or scoring systems be used for risk stratification by clinicians when they request a contrast-enhanced imaging study?
PC-AKI: Risk stratification; use of nephrotoxic medication
In hospitals which use sCr measurements for all patients before intravascular CM administration there is no benefit in using questionnaires for PC-AKI risk stratification.
In hospitals which use sCr measurements selectively, Choyke questionnaires may be used to identify patients with eGFR < 45 ml/min/1.73 m2 before intra-arterial CM administration with first pass renal exposure.
Level of evidence D
Risk prediction scores are only available for coronary angiography and/or percutaneous coronary intervention, and have only modest abilities, so cannot be recommended to stratify the risk of PC-AKI.
Level of evidence A
In CKD patients receiving CM, optimal nephrologic care involves minimising the use of nephrotoxic drugs.
Level of evidence D
ACE inhibitors and angiotensin receptor blockers do not have to be stopped before CM administration.
Level of evidence B
There is insufficient evidence to recommend withholding nephrotoxic drugs such as NSAIDs, antimicrobial agents or chemotherapeutic agents before CM administration.
Level of evidence C
Risk prediction models
No risk models have been produced yet for IV or IA CM administration with second pass renal exposure. For patients having coronary angiography (CA) or percutaneous coronary intervention (PCI), many different risk scores have been proposed to stratify the patient’s PC-AKI risk, and most include pre-procedural and procedural data. A model with only pre-procedural data  would be more practical for selecting suitable preventive measures. Risk scores should be verified in relation to improvements in clinical outcome. In clinical practice, a prediction rule would require a high discriminatory value, i.e. a C-statistic greater than 0.80 .
The best-known risk model is the eight-variable Mehran score , which has been studied in more than 15,000 patients and has been externally validated in multiple studies, but with variable C-statistic values of 0.57–0.85 [16, 18, 19, 20]. The Mehran score correlates relatively well with clinical outcomes . Newer risk scores with good discriminatory value, available in user-friendly calculators or smartphone applications, still need external validation . A recent systematic review of 16 risk models concluded that they had only modest predictive value  and a review and meta-analysis of 74 risk models noted their heterogeneity and concluded that further research was needed to evaluate the effect of such models on clinical care  (Table 1).
Question 6: Should nephrotoxic medication be withheld to reduce the risk of PC-AKI?
Optimal nephrologic care involves minimizing the use of nephrotoxic drugs where clinically possible . Many frequently prescribed medications, such as nonselective NSAIDs, selective Cox-2 inhibitors, several classes of antimicrobial agents and chemotherapeutic agents have nephrotoxic potential and can induce AKI .
There is little good quality data about the relationship between these drugs and PC-AKI . A retrospective cohort study showed that concurrent use of four or more nephrotoxic agents was significantly predictive for PC-AKI in patients given IV CM . A meta-analysis of PC-AKI incidence following CM-enhanced CT found that concurrent administration of NSAIDs was an independent risk factor for PC-AKI .
The effect of withholding angiotensin converting enzyme inhibitors (ACEI) and angiotensin-2 receptor blockers (ARB) in chronic users has been extensively evaluated. Multiple RCTs [30, 31] and observational studies gave conflicting results and are limited by small sample sizes and significant heterogeneity [32, 33, 34]. However, meta-analyses of RCTs found no lower risk . Withholding ACEI/ARB may be associated with a slightly lower risk of PC-AKI but the evidence is not sufficiently strong to recommend this (Table 1).
Question 7: What are the most cost- and time-effective protocols for oral and intravenous hydration to reduce the risk of PC-AKI?
Hydration as a preventive strategy for PC-AKI
Evidence for prevention of PC-AKI with IV saline hydration (volume expansion) comes from RCTs in patients who received intra-arterial (IA) CM during percutaneous intervention [35, 36, 37], and in patients who received bicarbonate hydration before IV enhanced emergency CTPA . One RCT evaluated the evidence for IA CM administration during CA . These studies found that, for both IA and IV CM administration, the incidence of PC-AKI was significantly lower in patients who received IV hydration compared to placebo, and that hydration prevented emergency dialysis . Significant differences for mortality or other adverse events were not found. There were few patients with severe renal impairment (eGFR < 30 ml/min/1.73 m2) in almost all studies. The recent AMACING trial showed that for patients with eGFR > 30 ml/min/1.73 m2 receiving IV CM there was no difference between no hydration and hydration in preventing PC-AKI .
Oral hydration versus intravenous saline hydration
PC-AKI prophylaxis: Hydration, drugs, renal replacement therapy
Preventive hydration should be used to reduce the incidence of PC-AKI in at-risk patients.
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 second pass renal exposure hydrate the patient with either (a) 3 ml/kg/h bicarbonate 1.4% (or 154 mmol/l solution) for 1 h before CM or (b) 1 ml/kg/h saline 0.9% for 3–4 h before and 4–6 h after CM.
Level of evidence D
For intra-arterial CM administration with first pass renal exposure hydrate the patient with either (a) 3 ml/kg/h bicarbonate 1.4% (or 154 mmol/l solution) for 1 h before CM followed by 1 ml/kg/h bicarbonate 1.4% (or 154 mmol/l) for 4–6 h after CM
or (b) 1 ml/kg/h saline 0.9% 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
In patients with severe heart failure (NYHA grade 3–4) or patients with end-stage renal failure (CKD grade V) preventive IV hydration should be individualized by the clinician responsible for patient care.
Level of evidence D
N-Acetylcysteine has not been conclusively shown to reduce the risk of PC-AKI in patients with eGFR < 45 ml/min/1.73 m2 receiving intravenous or intra-arterial CM, and its use is NOT recommended.
Level of evidence A
Giving short-term, high-dose statins to patients not already taking statins has not been shown to reduce the risk of PC-AKI in patients with eGFR < 45 ml/min/1.73 m2 receiving intravenous or intra-arterial CM, and its use is NOT recommended.
Level of evidence B
ACE inhibitors or angiotensin receptor blockers have not been shown conclusively to reduce the risk of PC-AKI in patients receiving intravenous or intra-arterial CM, and their use is NOT recommended.
Level of evidence B
Vitamin C has not been shown conclusively to reduce the risk of PC-AKI in patients receiving intravenous or intra-arterial CM, and its use is NOT recommended.
Level of evidence B
Renal replacement therapy
Renal replacement therapy has not been shown conclusively to reduce the risk of PC-AKI in patients receiving intravenous or intra-arterial CM, and its use is NOT recommended.
Level of evidence B
Intravenous hydration: saline versus bicarbonate
Normal saline (NaCl 0.9%) and sodium bicarbonate solution (1.4% or 154 mmol NaHCO3 in D5W) are the two most commonly studied crystalloid solutions. The rationale for using bicarbonate is that alkalinisation can reduce the formation of free reactive oxygen species . Initial studies favoured bicarbonate [53, 54, 55, 56], but this was not replicated in later studies [57, 58, 59, 60, 61, 62], so IV hydration with bicarbonate can be considered equivalent to normal saline.
There is no consensus on the optimal hydration regime. Most studies have compared bicarbonate given pre- and post-CM for less than 6 h  to longer duration saline pre- and post-CM protocols (12–24 h). In all studies, there are few patients with eGFR < 30 ml/min/1.73 m2, and evidence about whether short duration bicarbonate is better than long duration saline is conflicting [63, 64, 65, 66, 67, 68, 69, 70, 71]. There is limited evidence on whether pre-hydration only is inferior to pre- and post-hydration, and only one very short duration bicarbonate protocol has been evaluated [38, 72, 73].
Most studies have been performed in cardiac patients admitted for CA or PCI. Three studies evaluated hydration protocols in patients having contrast-enhanced CT, and did not favour bicarbonate over saline [38, 72, 74]. No studies were identified assessing the beneficial effect of other crystalloids. However, balanced crystalloid solutions, such as Ringer’s lactate, may be preferable in critical care populations, because they avoid the harmful effects of hyperchloraemic acidosis.
The CMSC considers that for IV and IA CM injection with second pass renal exposure either a short bicarbonate hydration regime before CM or a conventional protocol with saline given before and after CM may be used. For IA CM injection with first pass renal exposure conventional protocols with either bicarbonate or saline given before and after CM should be used (Table 2).
Forced diuresis versus conventional hydration
Newer approaches for patients with impaired left ventricular function combine controlled saline hydration with a forced high urinary flow rate to maintain euvolemia and avoid overhydration and several RCTs showed better results than conventional hydration protocols [75, 76, 77]. Other catheter-based strategies used left ventricular end-diastolic pressure or central venous pressure to guide hydration [78, 79]. In these RCTs the incidence of PC-AKI was lower than with standard IV hydration. Since the forced diuresis studies have heterogeneous populations, interventions and control hydration protocols, their findings cannot be pooled. The CMSC considers that there is not sufficient evidence to recommend forced diuresis.
In which patients should the hydration protocol be individualized?
There is no data to suggest that patients with severe renal impairment (CKD grade V) or severe heart failure (NYHA grade 3–4) should receive different hydration protocols. However, IV hydration with large volumes may exacerbate acute heart failure and induce pulmonary oedema . The opinion of the CMSC is that hydration protocols in these patients should be individualized for type, volume and duration.
Question 8: Which other strategies (pharmaceutical, vitamin, renal replacement therapy) have been proved effective in preventing PC-AKI?
Most recent RCTs or meta-analyses do not show a protective effect of NAc against PC-AKI following coronary or peripheral angiography [66, 80, 81, 82, 83, 84]. NAc also failed to affect clinical outcome in coronary or peripheral angiography  or to have a protective effect in CT [86, 87] or in patients with diabetes mellitus undergoing coronary or peripheral angiography [88, 89]. Comparative studies with NAc combined with saline or sodium bicarbonate protocols did not show any additional effect of protective effect of NAc [61, 90, 91, 92, 93]. However, more recent meta-analyses showed a benefit of NAc, with or without high-dose statins, when added to hydration for preventing PC-AKI [94, 95, 96].
Several meta-analyses showed lower overall PC-AKI rates with the use of high-dose, short-term statin treatment compared to controls [95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105]. Lower PC-AKI rates were also found in subgroups, such as older patients, patients with acute coronary syndromes and for high-dose statin regimes. Some of these meta-analyses showed a reduced need for RRT after statins, but no reduction in all-cause mortality [97, 102]. However, the US Agency for Healthcare Research and Quality (AHRQ) meta-analysis showed that the risk of PC-AKI was only significantly reduced when statins were added to hydration and NAc. A reduction in PC-AKI risk could not be shown when statins plus hydration were compared to hydration alone in patients not taking statins. The standard of evidence grade was low in both analyses .
Despite the many positive results, it is difficult to make a general recommendation for statins  because the patients studied were invariably cardiac, and a variety of statin and hydration protocols were used. Patients with CKD grade 3B–5 (eGFR < 45 ml/min/1.73 m2) are under-represented in the studies and results in these patients remain inconclusive [102, 103, 107, 108]. Most patients undergoing CA/PCI are already taking long-term statins, and results in these patients are unclear.
While the CMSC recognises the potential preventive effects of short-term statins, it does not advise the use of short-term, high-dose statins as a single strategy for preventing PC-AKI (Table 2).
RAAS blockade: ACE inhibitors and angiotensin-II receptor blockers
Administration of renin–angiotensin–aldosterone system (RAAS) blockade as a preventive measure for patients not taking these drugs did not show a significant effect on the incidence of PC-AKI in recent meta-analyses [32, 34] (Table 2).
The majority of RCTs or meta-analyses do not demonstrate a protective effect of vitamin C against PC-AKI in patients with CKD predominantly undergoing coronary angiography [109, 110, 111] or any benefit of the use of vitamin C, NAc or a combination of both over the standard hydration regimen in preventing PC-AKI [112, 113] (Table 2). Combining vitamin C with pentoxifylline also failed to show an advantage . Only two publications [115, 116] have shown a protective effect of vitamin C in patients with CKD undergoing CA.
Renal replacement therapy (RRT)
There is no convincing evidence in favour of preventive haemodialysis or RRT alone [117, 118, 119] or combined with hydration  in patients with CKD, predominantly undergoing CA (Table 2). There is no evidence of an increased risk of permanent anuria in patients on peritoneal dialysis undergoing CA . There is a single study showing better late-stage (day 5–30) renal protection against PC-AKI with simultaneous haemodialysis .
The data on the protective effects of several agents, such as trimatizidine [123, 124], theophylline [95, 125, 126, 127], alprostadil [128, 129], nebivolol , fenoldopam  and iloprost , is not conclusive and does not support recommending their use to reduce the risk of PC-AKI.
Question 9: Should administration of metformin be adapted to reduce the risk of metformin-associated lactic acidosis in patients with type 2 diabetes mellitus scheduled to receive intravascular contrast media?
Metformin is the standard drug for monotherapy of type 2 diabetes mellitus . The effect of CM on the risk of metformin-associated lactic acidosis is indirect, since an episode of AKI following intravascular CM administration may lead to metformin accumulation. The use of metformin in patients with eGFR 30–59 ml/min/1.73 m2 is considered safe if doses are reduced appropriately [134, 135]. Limiting the metformin dose to a maximum of 2000 mg/day for eGFR 45–60 ml/min/1.73 m2 and to a maximum of 1000 mg/day for eGFR 30–44 ml/min/1.73 m2 has been recommended. In patients with eGFR 30–59 ml/min/1.73 m2 metformin drug levels remain within therapeutic ranges. For patients with eGFR < 30 ml/min/1.73 m2 metformin administration is not approved.
Multiple studies and meta-analyses have shown that the risk of lactic acidosis is very low and linked more to the underlying disease and possible co-morbidities rather than the use of metformin [134, 136, 137]. Because of the lack of published evidence on metformin and CM, early guidelines about the need to stop metformin before intravascular CM were based on consensus, and were strict [138, 139]. As the low risk of lactic acidosis became apparent, guidelines have become less restrictive .
Metformin administration, dialysis schedules
Metformin administration in patients at risk of PC-AKI
Note that these recommendations may deviate from current EMA/FDA recommendations.
Patients with eGFR > 30 ml/min/1.73 m2 and no evidence of AKI receiving either intravenous CM or intra-arterial CM with second pass renal exposure: continue taking metformin normally.
Patients (a) with eGFR < 30 ml/min/1.73 m2 receiving either intravenous CM or intra-arterial CM with second pass renal exposure or (b) receiving intra-arterial CM with first pass renal exposure or (c) with AKI: stop taking metformin from the time of CM administration: measure eGFR within 48 hours and restart metformin if renal function has not changed significantly.
Level of evidence D
Dialysis schedules in relation to CM administration
It is not necessary to adapt the timing of intravascular CM administration in relation to the dialysis schedule in patients undergoing chronic dialysis or haemofiltration, but it may be done to minimise volume overload.
Level of evidence D
Question 10: Should the timing of CM administration be adapted to the schedule of haemodialysis or haemofiltration sessions in patients on renal replacement therapy?
Iodine-based CM can be safely removed by haemodialysis (HD) or haemofiltration (HF). Many factors influence the effectiveness of HD, such as flow rate of blood and dialysate, dialysis membrane permeability, HD duration, and CM characteristics such as molecular size, protein binding, hydrophilicity and electrical charge .
Although HF concomitant with radiological procedures has been shown to be feasible and well tolerated [143, 144], the fractional removal of iodine-based CM contrast agents is modest and several HF or HD sessions are needed to remove 95% of the administered CM . Also, there is no evidence for the necessity of emergency HD after administration of iodine-based CM in patients on chronic HD . However, to avoid volume overload, CM administration may be synchronised with scheduled HF or HD (Table 3).
Assessment of the risk of PC-AKI before intravascular CM is administered is best done by measuring eGFR but the alternative of a questionnaire for patients detects most patients with eGFR less than 45 ml/min/1.73 m2. Volume expansion with normal saline or sodium bicarbonate remains the mainstay of PC-AKI prevention, but there is still uncertainty about the optimal protocol. The additional benefit of a number of drugs, such as N-acetylcysteine, statins, ACE inhibitors and angiotensin-II receptor blockers, and vitamin C in preventing PC-AKI has not been proved conclusively. Stopping nephrotoxic medications appears to be of limited value in preventing PC-AKI. Recommendations for discontinuing metformin when CM is given have been relaxed and now only apply to patients with eGFR < 30 ml/min/1.73 m2 receiving IV CM or IA CM with second pass renal exposure, and to all patients receiving IA CM with first pass renal exposure or who have AKI. There is no need to adapt dialysis schedules in patients being given intravascular CM.
ESUR CMSC guideline (version 10) for post-contrast acute kidney injury (PC-AKI)
Post-contrast acute kidney injury (PC-AKI) is defined as an increase in serum creatinine ≥ 0.3 mg/dl (or ≥ 26.5 μmol/l), or ≥ 1.5 times baseline, within 48–72 h of intravascular administration of a contrast medium.
Intra-arterial injection with first pass renal exposure indicates that contrast medium reaches the renal arteries in a relatively undiluted form, e.g. injection into the left heart, thoracic and suprarenal abdominal aorta or the renal arteries.
Intra-arterial injection with second pass renal exposure indicates that contrast medium reaches the renal arteries after dilution either in the pulmonary or peripheral circulation e.g. injection into the right heart, pulmonary artery, carotid, subclavian, coronary, mesenteric or infra-renal arteries.
Measurement of renal function
• Estimated glomerular filtration rate (eGFR), calculated from the serum creatinine, is recommended to estimate renal function before administration of contrast medium.
• In adults ≥ 18 years, the CKD-EPI formula to estimate GFR is recommended.
eGFR (ml/min/1.73 m2) =
Female sCr ≤ 62 μmol/l: 144 × (sCr/62)−0.329 × 0.993Age
Female sCr > 62 μmol/l: 144 × (sCr/62)−1.209 × 0.993Age
Male sCr ≤ 80 μmol/l: 141 × (sCr/80)−0.411 × 0.993Age
Male sCr > 80 μmol/l: 141 × (sCr/80)−1.209 × 0.993Age
(sCr in μmol/l; age in years)
All equations × 1.159 if African American race
• In children, the revised Schwartz formula to estimate GFR is recommended,
eGFR (ml/min/1.73 m2) = 36.5 × Length/sCr (sCr in μmol/l; length in cm)
Note: Neither serum nor plasma creatinine is an ideal indicator of renal function and may miss decreased renal function.
Renal adverse reactions to iodine-based contrast media
RISK FACTORS FOR PC-AKI
• eGFR less than 45 ml/min/1.73 m2 before intra-arterial contrast medium administration with first pass renal exposure or in ICU patients
• eGFR less than 30 ml/min/1.73 m2 before intravenous contrast medium or intra-arterial contrast medium administration with second pass renal exposure
• Known or suspected acute renal failure
• Intra-arterial contrast medium administration with first pass renal exposure
• Large doses of contrast medium given intra-arterially with first pass renal exposure
• High osmolality contrast media
• Multiple contrast medium injections within 48-72h
Time of referral
MEASUREMENT OF RENAL FUNCTION
• Measure eGFR before administering intravascular iodine-based contrast medium
either (a) In all patients
or (b) In patients who have a history of
- Renal disease (eGFR < 60 ml/min/1.73 m2)
- Kidney surgery
- Diabetes mellitus
• Timing of eGFR measurement
- Within 7 days before contrast medium administration in patients with an acute disease, an acute deterioration of a chronic disease or who are hospital inpatients
- Within 3 months before contrast medium administration in all other patients
Identify at-risk patients (see above), if possible:
• Determine eGFR if the procedure can be deferred until the result is available without harm to the patient.
• If eGFR cannot be obtained, follow the protocols for patients with eGFR less than 45 ml/min/1.73 m2 for intra-arterial administration with first pass renal exposure and eGFR less than 30 ml/min/1.73 m2 for intravenous and intra-arterial administration with second pass renal exposure as closely as clinical circumstances permit.
Before the examination
At-risk patients (see above)
• Consider an alternative imaging method not using iodine-based contrast media
• Intravenous saline and bicarbonate have similar efficacy for preventive hydration
• For intravenous contrast media administration and intra-arterial contrast media administration with second pass renal exposure hydrate the patient either with intravenous sodium bicarbonate 1.4% (or 154 mmol/l in dextrose 5% water): 3 ml/kg/h for 1 h before contrast medium or with intravenous saline 0.9%, 1 ml/kg/h for 3–4 h before and 4–6 h after contrast medium
• For intra-arterial contrast media administration with first renal exposure hydrate the patient either with intravenous sodium bicarbonate 1.4% (or 154 mmol/l in dextrose 5% water): 3 ml/kg/h for 1 h before and 1 ml/kg/h for 4–6 h after contrast medium or with intravenous saline 0.9%, 1 ml/kg/h for 3–4 h before and 4–6 h after contrast medium
• The clinician responsible for patient care should individualize preventive hydration in patients with severe congestive heart failure (NYHA grade 3–4) or patients with end-stage renal failure (eGFR < 15 ml/min/1.73 m2)
• Oral hydration is not recommended as the sole method of preventive hydration
At-risk patients (see above)
• Consider an alternative imaging method not using iodine-based contrast media
• Use preventive hydration before contrast medium administration (see ‘Elective Examination’ for protocols)
Time of examination
• Use low or iso-osmolar contrast media
• Use the lowest dose of contrast medium consistent with a diagnostic result
• For intra-arterial contrast medium administration with first pass renal exposure keep either the ratio CM dose (in gram I)/absolute eGFR (in ml/min) < 1.1 or the ratio CM volume (in ml)/eGFR (in ml/min/1.73 m2) < 3.0 (assuming a contrast medium concentration of 350 mg iodine/ml)
After the examination
• Continue preventive hydration if appropriate (see protocols above)
• Determine eGFR 48 h after administration of contrast medium
• If at 48 h there is a diagnosis of PC-AKI, monitor the patient clinically for at least 30 days and determine eGFR at regular intervals
Note: No pharmacological prophylaxis (with statins, renal vasodilators, receptor antagonists of endogenous vasoactive mediators or cytoprotective drugs) has been shown to offer consistent protection against PC-AKI.
Patients with diabetes mellitus taking metformin
• Patients with eGFR > 30 ml/min/1.73 m2 and no evidence of AKI receiving either intravenous or intra-arterial iodine-based contrast medium with second pass renal exposure: Continue taking metformin normally.
• Patients (a) with eGFR < 30 ml/min/1.73 m2 receiving either intravenous or intra-arterial contrast medium with second pass renal exposure or (b) receiving intra-arterial contrast medium with first pass renal exposure or (c) with AKI:
Stop taking metformin from the time of contrast medium administration. Measure eGFR within 48 h and restart metformin if renal function has not changed significantly.
Dialysis and contrast medium administration
• All iodine-based contrast media can be removed by haemodialysis or peritoneal dialysis.
• There is no evidence that haemodialysis protects patients with normal or impaired renal function from PC-AKI.
• In all patients, avoid osmotic and fluid overload.
PATIENTS ON DIALYSIS
Patients on haemodialysis
• Co-ordinating the time of the iodine-based contrast medium injection with the haemodialysis session is unnecessary
• Extra haemodialysis session to remove iodine-based contrast medium is unnecessary
Patients on continuous ambulatory peritoneal dialysis
Haemodialysis to remove iodine-based contrast medium is unnecessary
The authors state that this work has not received any funding.
Compliance with ethical standards
The scientific guarantor of this publication is Prof. Henrik S. Thomsen.
Conflict of interest
Aart van der Molen has received incidental payments for lectures and chairmanships at scientific meetings for contrast agent safety related issues (contrast agent reactions, Gd-retention) from GE, Bayer, Bracco and Guerbet.
Fulvio Stacul has received lecture fees from Bracco and Guerbet.
Olivier Clément has received lecture fees from Bracco and Guerbet.
The other authors of this manuscript declare no relationships with any companies whose products and services may be related to the subject matter of this article.
Statistics and biometry
No complex statistical methods were necessary for this paper.
Written informed consent was not required for this study because this is a special paper based on other publications. Thus informed consent is not necessary.
Institutional review board approval was not required because it is a retrospective study based on other studies.
• multicentre study
- 3.Contrast Media Safety Committee ESUR. Guidelines on Contrast Media v9. CMSC, 2014. http://www.esur-cm.org/index.php/en/. 15 December 2017
- 4.Brouwers M, Kho ME, Browman GP, on behalf of the AGREE Next Steps Consortium et al (2010) AGREE II: Advancing guideline development, reporting and evaluation in healthcare. Can Med Assoc J 182:E839–E842Google Scholar
- 6.OCEBM Levels of Evidence Working Group. The Oxford 2011 Levels of Evidence. Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/index.aspx?o=5653. Accessed 15 December 2017
- 14.Van der Molen AJ, Geenen RWF, Dekkers HM et al for the Radiological Society of the Netherlands (RSTN). Guideline safe use of contrast media, part 1. Vught, RSTN: 2017. https://www.radiologen.nl/secties/nvvr/documenten/richtlijn-veilig-gebruik-van-contrastmiddelen-deel-1-full-english. Accessed 15 December 2017
- 24.Allen DW, Ma B, Leung KC et al (2017) Risk prediction models for contrast-induced acute kidney injury accompanying cardiac catheterization: systematic review and meta-analysis. Can J Cardiol 33(6):724-736
- 25.Dutch Federation of Nephrology. Guideline diagnosis and management of chronic kidney disease 2016. https://www.nefro.nl/richtlijnen/diagnostiek-en-behandeling-van-chronische-nierschade-voorlopige-richtlijn-2016-0. Accessed 15 December 2017
- 28.Ho YF, Hsieh KL, Kung FL, et al (2015) Nephrotoxic polypharmacy and risk of contrast medium-induced nephropathy in hospitalized patients undergoing contrast-enhanced CT. AJR Am J Roentgenol 205:703–708Google Scholar
- 31.Bainey KR, Rahim S, Etherington K, CAPTAIN Investigators et al (2015) Effects of withdrawing vs. continuing renin-angiotensin blockers on incidence of acute kidney injury in patients with renal insufficiency undergoing cardiac catheterization: results from the angiotensin converting enzyme inhibitor/angiotensin receptor blocker and contrast induced nephropathy in patients receiving cardiac catheterization (CAPTAIN) trial. Am Heart J 170:110–116PubMedGoogle Scholar
- 36.Luo Y, Wang X, Ye Z, et al (2014) Remedial hydration reduces the incidence of contrast-induced nephropathy and short-term adverse events in patients with ST-segment elevation myocardial infarction: a single-center, randomized trial. Intern Med 53:2265–2272Google Scholar
- 40.Nijssen EC, Rennenberg RJ, Nelemans PJ et al (2017) Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. Lancet 389:1312–1322PubMedGoogle Scholar
- 50.Cheungpasitporn W, Thongprayoon C, Brabec BA, Edmonds PJ, O'Corragain OA, Erickson SB (2014) Oral hydration for prevention of contrast-induced acute kidney injury in elective radiological procedures: a systematic review and meta-analysis of randomized controlled trials. N Am J Med Sci 6:618–624PubMedPubMedCentralGoogle Scholar
- 55.Ozcan EE, Guneri S, Akdeniz B et al (2007) Sodium bicarbonate, N-acetylcysteine, and saline for prevention of radiocontrast-induced nephropathy. A comparison of 3 regimens for protecting contrast-induced nephropathy in patients undergoing coronary procedures. A single-center prospective controlled trial. Am Heart J 154:539–544PubMedGoogle Scholar
- 57.Adolph E, Holdt-Lehmann B, Chatterjee T et al (2008) Renal Insufficiency Following Radiocontrast Exposure Trial (REINFORCE): a randomized comparison of sodium bicarbonate versus sodium chloride hydration for the prevention of contrast-induced nephropathy. Coron Artery Dis 19:413–419PubMedGoogle Scholar
- 65.Chong E, Poh KK, Lu Q et al (2015) Comparison of combination therapy of high-dose oral N-acetylcysteine and intravenous sodium bicarbonate hydration with individual therapies in the reduction of Contrast-induced Nephropathy during Cardiac Catheterisation and Percutaneous Coronary Intervention (CONTRAST): a multi-centre, randomised, controlled trial. Int J Cardiol 201:237–242PubMedGoogle Scholar
- 66.Hafiz AM, Jan MF, Mori N et al (2012) Prevention of contrast-induced acute kidney injury in patients with stable chronic renal disease undergoing elective percutaneous coronary and peripheral interventions: randomized comparison of two preventive strategies. Catheter Cardiovasc Interv 79:929–937PubMedGoogle Scholar
- 67.Koc F, Ozdemir K, Altunkas F et al (2013) Sodium bicarbonate versus isotonic saline for the prevention of contrast-induced nephropathy in patients with diabetes mellitus undergoing coronary angiography and/or intervention: a multicenter prospective randomized study. J Investig Med 61:872–877PubMedGoogle Scholar
- 72.Kooiman J, Sijpkens YW, de Vries JP et al (2014) A randomized comparison of 1-h sodium bicarbonate hydration versus standard peri-procedural saline hydration in patients with chronic kidney disease undergoing intravenous contrast-enhanced computerized tomography. Nephrol Dial Transplant 29:1029–1036PubMedGoogle Scholar
- 73.Kooiman J, de Vries JP, van der Heyden J et al (2014) Randomized trial of 1-hour sodium bicarbonate vs. Standard saline hydration in patients with chronic kidney disease undergoing intra-arterial contrast administration [abstr]. Circulation 130:A17645Google Scholar
- 74.Kama A, Yilmaz S, Yaka E et al (2014) Comparison of short-term infusion regimens of N-acetylcysteine plus intravenous fluids, sodium bicarbonate plus intravenous fluids, and intravenous fluids alone for prevention of contrast-induced nephropathy in the emergency department. Acad Emerg Med 21:615–622PubMedGoogle Scholar
- 76.Marenzi G, Ferrari C, Marana I et al (2012) Prevention of contrast nephropathy by furosemide with matched hydration: the MYTHOS (Induced Diuresis With Matched Hydration Compared to Standard Hydration for Contrast Induced Nephropathy Prevention) trial. JACC Cardiovasc Interv 5:90–97PubMedGoogle Scholar
- 77.Usmiani T, Andreis A, Budano C et al (2016) AKIGUARD (Acute Kidney Injury GUARding Device) trial: in-hospital and one-year outcomes. J Cardiovasc Med 17:530–537Google Scholar
- 88.Berwanger O, Cavalcanti AB, Sousa AM et al (2013) Acetylcysteine for the prevention of renal outcomes in patients with diabetes mellitus undergoing coronary and peripheral vascular angiography: a substudy of the acetylcysteine for contrast-induced nephropathy trial. Circ Cardiovasc Interv 6:139–145PubMedGoogle Scholar
- 95.Ali-Hassan-Sayegh S, Mirhosseini SJ, Ghodratipour Z et al (2017) Strategies preventing contrast-induced nephropathy after coronary angiography: a comprehensive meta-analysis and systematic review of 125 randomized controlled trials. Angiology 68:389–413Google Scholar
- 98.Cheungpasitporn W, Thongprayoon C, Kittanamongkolchai W, et al (2015) Periprocedural effects of statins on the incidence of contrast-induced acute kidney injury: a systematic review and meta-analysis of randomized controlled trials. Ren Fail 37:664–671Google Scholar
- 99.Li H, Wang C, Liu C, Li R, Zou M, Cheng G (2016) Efficacy of short-term statin treatment for the prevention of contrast-induced acute kidney injury in patients undergoing coronary angiography/percutaneous coronary intervention: a meta-analysis of 21 randomized controlled trials. Am J Cardiovasc Drugs 16:201–219PubMedGoogle Scholar
- 109.Brueck M, Cengiz H, Hoeltgen R et al (2013) Usefulness of N-acetylcysteine or ascorbic acid versus placebo to prevent contrast-induced acute kidney injury in patients undergoing elective cardiac catheterization: a single-center, prospective, randomized, double-blind, placebo-controlled trial. J Invasive Cardiol 25:276–283PubMedGoogle Scholar
- 111.Li R, Chen H (2012) Prevention of contrast-induced nephropathy with ascorbic acid. Heart 98:E211Google Scholar
- 112.Albabtain MA, Almasood A, Alshurafah H, Alamri H, Tamim H (2013) Efficacy of ascorbic acid, N-acetylcysteine, or combination of both on top of saline hydration versus saline hydration alone on prevention of contrast-Induced nephropathy: a prospective randomized study. J Interv Cardiol 26:90–96PubMedGoogle Scholar
- 114.Shakeryan F, Sanati H, Fathi H et al (2013) Evaluation of combination therapy with vitamin C and pentoxifylline on preventing kidney failure secondary to intravenous contrast material in coronary angioplasty. Iran Heart J 14:17–21Google Scholar
- 116.Wang XT, Yan J, Li L, Su Q (2014) Anti-oxidative vitamin for the prevention of contrast-induced acute kidney injury in patients with chronic kidney disease: meta-analysis of randomized controlled trials. Exp Clin Cardiol 20:1385–1410Google Scholar
- 133.Inzucchi SE, Bergenstal RM, Buse JB et al (2015) Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 38:140–149PubMedGoogle Scholar
- 137.Salpeter SR, Greyber E, Pasternak GA, Salpeter EE (2010) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 14:CD002967Google Scholar
- 139.Thomsen HS, Morcos SK, ESUR CMSC (1999) Contrast media and metformin: guidelines to diminish the risk of lactic acidosis in non-insulin-dependent diabetics after administration of contrast media. Eur Radiol 9:738-740Google Scholar
- 140.Food and Drug Administration (FDA) (2016) FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm. Accessed 15 December 2017
- 141.ACR Committee on Drugs and Contrast Media (2017) ACR manual on contrast media, v10.3. American College of Radiology. https://www.acr.org/-/media/ACR/Files/Clinical-Resources/Contrast_Media.pdf. Accessed 15 December 2017
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