Session Name: Proffered papers - CT Scanning Presentation Title: Efforts to Prevent Contrast-Induced Acute Kidney Injury. Presenter Name: Dr Sarah Constantine FRANZCR The Queen Elizabeth Hospital University of Adelaide, SA.

Session Name: Proffered papers - CT Scanning The presenter has advised that the following presentation will NOT include discussion on any commercial products or service and that there are NO financial interests or relationships with any of the Commercial Supporters of the 2014 Combined Scientific Meeting.

Efforts to Prevent Contrast-Induced Acute Kidney Injury. Dr Sarah Constantine FRANZCR The Queen Elizabeth Hospital University of Adelaide, SA.

Contrast-induced acute kidney injury. CI-AKI is defined as an acute decrease in renal function, occurring within 3 days of administration of iodinated contrast, (in the absence of an alternative aetiology).1 transient event serum creatinine peaks at approx. 72 hours slowly returns to normal over 2 weeks small number will progress to established renal failure 1. RANZCR Guidelines 2009

RANZCR Guidelines introduced in 2009 provide detailed information for the management of patients with impaired renal function who require iodinated contrast clinician and radiologist awareness of updated guidelines is variable Our College has guidelines for the administration of of iodinated contrast. The current guidelines were formalised in March 2009, and are based on guidelines from other international Colleges, as well as numerous published studies. They provide detailed, evidence-based guidelines for the management of patients with impaired renal function who require iodinated contrast as part of a radiological study or procedure. The recommendations have changed over the years, and the awareness of both radiologists and referrers of these changes seems quite variable. One of the most important changes from the previous guidelines is the use of the estimated glomerular filtration rate which provides a more accurate measure of a patient’s renal function than the serum creatinine alone. This is because it takes into account the patient’s age, gender and race, as well as their serum creatinine level.

Contrast-induced acute kidney injury. 15% of ICU patients2, 1.5% of unselected patients3 a deterioration in serum markers of renal function after administration of iodinated contrast is very common almost always an “alternative aetiology” - or compounding factors 2. Hoste Intensive Care Med 2011 3. Laskey J Am Coll Cardiol 2007

Risk Factors for CI-AKI. advanced age (over 75 years) pre-existing renal disease prolonged hypotension (systolic BP less than 80mmHg for 1 hour or more within 48 hours of contrast administration) congestive cardiac failure diabetes mellitus cirrhosis multiple myeloma

Risk Factors for CI-AKI. dehydration anaemia low serum albumin (< 35 g/L) medications – ACE inhibitors, angiotensin II blockers, NSAIDs, diuretics, nephrotoxic antibiotics eg gentamicin

Reducing the risk of CI-AKI. identify + modify risk factors (where possible) defer scan alternative imaging technique involve renal physicians monitor renal function

Methods of Risk Reduction in CI-AKI. adequate hydration4 – easy, cheap, quick, safe, take care in CCF volume of contrast5 – use the minimum necessary to obtain a diagnostic scan 4. Balemans Radiology 2012 5. Gurm Am J Coll Cardiol 2011

The Queen Elizabeth Hospital 350 bed adult teaching hospital only renal transplant unit in SA until 2010, large renal medicine/dialysis unit busy emergency department, medical and surgical units, intensive care unit I work at the QEH, which is a 350 bed adult teaching hospital in the western suburbs of Adelaide, about 10 km from the CBD. Until recently, the QEH was SA’s only renal transplant hospital, and has a large renal medicine unit, as well as a busy emergency department, medical , surgical and intensive care units. As such, we are possibly more aware than other Adelaide hospitals of the need to protect renal function in our patient population.

Renal Protection Audit 2010 retrospective audit of CT scans in 2010 (13 270 scans, 6 829 (52%) with IV contrast) identified patients with eGFR ≤ 60 mL/min/1.73m2 who received contrast (957, 7.2%) patients on long term dialysis (61) and those who died within 24 hours (2) were excluded data collected on a total of 894 patients To evaluate our efforts in preventing CIN, a retrospective audit of CT scans performed in 2010 was undertaken. We have 2 multislice CT scanners which service the hospital inpatients and outpatients, as well as a limited number of referrals from local GPs and specialists. The patients with an eGFR of 60 or less were identified, who received an intravenous contrast injection as part of their CT scan. Through a review of the hospital computer systems (OACIS), radiology reports and patient case notes, it was recorded which patients received a renal protection protocol, and the renal function (where available) was recorded at 24, 48 and 72 hours post injection. Patients on dialysis were excluded as their serum creatinine/eGFR fluctuates wildly with dialysis, and there is usually no concern about preserving any renal function in this group. Patients who died within 24 hours of their scan were also excluded as there could not be any follow up data.

Results 7.2% were contrast scans performed on renally-impaired patients despite these patients having Stage 3, 4 or 5 Chronic Kidney Disease6, only 18% received renal protection 59% of patients did not have their renal function rechecked within the danger period 7.2% of all CT scans were contrasted scans performed on renally-impaired patients One third were CT angiograms, which requires a higher contrast load than non-angiographic studies. Despite these patients having suboptimal renal function (Stage 3, 4 or 5 Chronic Kidney Disease3), only 18% received renal protection. Renal protection was considered to have been given if: it was reported as such in the radiology report, the renal protection form was filled out and in the case notes, or a reference was made in the medical or nursing notes to renal protection associated with the IV contrast and a corresponding fluid and/or NAC order was filled out. It was reassuring that a higher percentage of patients receiving a higher contrast dose received renal protection, but the number was still low. Almost 2/3 of all patients did not have a blood test within 3 days of the scan to recheck renal function. 6. Adair W Clin Radiol 2006

Results mean eGFR stable for most groups very large standard deviations No renal protection Renal protection The mean eGFR in each patient group remained stable over 72 hours, whether renal protection was provided or not. Amongst the patients in each group, however, there were extreme fluctuations in eGFR, with some patients having a marked drop in renal function, while others showed a marked improvement. I suspect that dehydration had a significant impact in several of these cases.

Results  Serum creatinine ≥ 25% Renal Protection Required Dialysis eGFR 45 – 60 17/601 = 2.8% 2/17 = 11% eGFR 30 – 44 10/252 = 4% 3/10 = 30% 2 (1 RP) eGFR < 30 6/41 = 14.6% 3/6 = 50% 2 (no RP) most patients had numerous risk factors of a decrease in renal function eg sepsis, diabetes several were also on potentially nephrotoxic drugs eg gentamicin Although we now use eGFR as a measure of renal function, CIN is still defined in terms of serum creatinine as a rise of 25% or more. As expected, the high risk group had the most patients whose renal function deteriorated significantly; 15% compared with 4% in group B and 3% in group A. Renal protection protocols were less protective in the higher risk group than the lower risk group. Only one patient who had renal protection required dialysis.

Results 1 patient died of renal failure 5 weeks after a contrast scan 2 patients became dialysis-dependent after a contrast scan 0.3% of cases studied 1 patient died of renal failure 5 weeks after his contrasted scan. He was also on gentamicin, and was diabetic on metformin. He was in group A with an initial eGFR of 56, and his renal function was not rechecked until 72 hours after his scan, when his eGFR was 17. He did receive renal protection. 1 patient who became dialysis dependent was in group C, with a baseline eGFR of 29. The other had no past history of renal impairment, but had a long ICU stay for the admission diagnosis of rhabdomyolysis, which was the initial cause of his deteriorated renal function. Neither of these patients received renal protection.

Are doing our best to prevent AKI? NO! inadequate renal follow up under utilization of renal protection ?? overuse of IV contrast 60% of patients do not have their renal function followed up - ? Assumed protection will work Low number of patients receiving renal protection – partly due to creatinine being used as measure of renal function, giving a false sense of security, especially in the elderly. Whether IV contrast was indicated, or another test could have been substituted is beyond the limitations of this study

Conclusion CI-AKI is a complicated issue a number of at-risk patients are not being adequately managed new procedures and a more formalised protocol

How Can We Improve? use eGFR, not serum creatinine as a measure of renal function Check the eGFR not the serum creatinine for each patient when required. At the QEH, we are now using this stamp, which is placed in the patient’s case notes, and on the back of the request form. We encourage all radiologists to include this information in the report.

SA Renal Network

7. SA Renal Network 2010

Possible Risk Reduction in CI-AKI. N-acetylcysteine8 – conflicting evidence as to its success, does no harm, expensive sodium bicarbonate9 – thought to be effective by some authors 8. Sergie Catheter Cardiovasc Interv 2012 9. Hiremath Nephrol Dial Transplant 2010

Renal Protection Audit 2012 retrospective audit of CT scans in 2012 (13 165 scans, 6 435 (49%) with IV contrast) identified patients with eGFR ≤ 60 mL/min/1.73m2 who received contrast (903, 6.9%) patients on long term dialysis (27) and those who died within 24 hours (4) were excluded data collected on a total of 872 patients To evaluate our efforts in preventing CIN, a retrospective audit of CT scans performed in 2010 was undertaken. We have 2 multislice CT scanners which service the hospital inpatients and outpatients, as well as a limited number of referrals from local GPs and specialists. The patients with an eGFR of 60 or less were identified, who received an intravenous contrast injection as part of their CT scan. Through a review of the hospital computer systems (OACIS), radiology reports and patient case notes, it was recorded which patients received a renal protection protocol, and the renal function (where available) was recorded at 24, 48 and 72 hours post injection. Patients on dialysis were excluded as their serum creatinine/eGFR fluctuates wildly with dialysis, and there is usually no concern about preserving any renal function in this group. Patients who died within 24 hours of their scan were also excluded as there could not be any follow up data. 24

Results  Serum creatinine ≥ 25% Renal Protection Required Dialysis eGFR 45 – 60 28/682 = 4.1% [2.8%] 25/28 = 89% [11%] 0 [0] eGFR 30 – 44 16/174 = 9.2% [4%] 10/16 = 63% [30%] 2 (no RP) [2, 1RP] eGFR < 30 3/20 = 15% [14.6%] 0/3 = 100% [50%] 2 (no RP) [2, no RP] most patients had numerous risk factors of a decrease in renal function eg sepsis, diabetes several were also on potentially nephrotoxic drugs eg gentamicin Although we now use eGFR as a measure of renal function, CIN is still defined in terms of serum creatinine as a rise of 25% or more. As expected, the high risk group had the most patients whose renal function deteriorated significantly; 15% compared with 4% in group B and 3% in group A. Renal protection protocols were less protective in the higher risk group than the lower risk group. Only one patient who had renal protection required dialysis.

Results 1 patient died of renal failure 4 weeks after a contrast scan 4 patients had significantly and permanently impaired renal function after a contrast scan 0.5% of cases studied 1 patient died of renal failure 5 weeks after his contrasted scan. He was also on gentamicin, and was diabetic on metformin. He was in group A with an initial eGFR of 56, and his renal function was not rechecked until 72 hours after his scan, when his eGFR was 17. He did receive renal protection. 1 patient who became dialysis dependent was in group C, with a baseline eGFR of 29. The other had no past history of renal impairment, but had a long ICU stay for the admission diagnosis of rhabdomyolysis, which was the initial cause of his deteriorated renal function. Neither of these patients received renal protection.

Renal Protection Audits did not take into account the indications for scanning decision to give contrast was based on the clinical indication and patient’s renal function combined

Results similar numbers of patients scanned in each year patient group was slightly older in 2012 (mean age 76 years vs 74 years 2010) around 40% of all patients were referred by 3 units: haematology/oncology, urology, vascular surgery

2012 group was lower risk over all than 2010 group There were far fewer patients in the high and very high risk groups in 2012.

Results after the introduction of a targeted renal protection protocol, there was a very significant increase in the number of patients being pre-hydrated (80% vs 19%) more patients had their renal function rechecked after contrast administration 25% of high or very high risk patients still did not have their eGFR rechecked

Results the use of the renal protection protocol was found to be efficacious in those patients with an eGFR of < 50 (p = 0.008) there was no efficacy in those with an eGFR of 50 and over unless they were hypotensive the most significant risk factors for developing AKI were hypotension (P< 0.001) and CCF

Results 4% of patients in 2010 and 7% of patients in 2012 developed AKI almost all of these patients had unstable renal function prior to contrast administration

Literature Review 750 patients with an eGFR < 60 who had an iodinated IV contrast scan they found IV hydration to be effective in protecting against AKI they also identified heart failure, low BMI and repeated doses of contrast to be significant risk factors 4. Balemans Radiology 2012

Literature Review compared contrast and non-contrast scans in 20 000, using propensity score analysis to remove selection bias they found patients to be at risk of AKI only if their serum creatinine was > 130 no association with the volume or concentration of contrast they also identified unstable renal function (improving AND declining) and loop diuretics as significant risk factors 10. Davenport Radiology 2013

Literature Review contrasted CT scans in 28 000 patients with stable renal function they found that using the eGFR measurement was more reliable than serum creatinine measurements for screening patients at risk of AKI 11. Davenport Radiology 2013

Recommendations screen all patients referred for contrasted CT history of renal disease history of cardiac impairment history of diabetes patient age 75 years and older if no history of the above, then a biochemical renal function screen is not necessary

Recommendations eGFR check for patients with any of the 4 main risk factors utilise the “risk score” to determine level of hydration/renal protection required liase with referrers to ensure renal function is checked within 72 hours of contrast administration

Contrast Dose to Cr Ratio Cigarroa formula3: 5ml/kg Cr (mg/dL) in patients with normal renal function, a ratio of 1:1 is considered safe, higher ratios are associated with a higher risk increasing evidence that this is effective ratio in Australia - 88.4 : 1 (μmol/L) 3. Laskey J Am Coll Cardiol 2007

Contrast Dose to GFR Ratio. iodinated contrast has linear pharmacokinetics: systemic clearance of contrast equals glomerular filtration rate 12. Nyman Acta Radiol 2005

Contrast Dose to Cr CL Ratio Author Ratio Low Risk High Risk Laskey et al3 volume CrCL Not stated ≥ 3.7 Gurm et al5 < 2 > 3 Altmann et al13 ≤ 6 (4%) > 6 (14%) Nyman et al12 gm-Iodine eGFR < 1 (2%) > 1 (25%) Nyman et al14 < 1 (3%) ≥1 (25%)

Results “safe” ratio was not able to be determined low contrast doses lack of biochemical follow-up data

Contrast Dose vs Creatinine Clearance

Summary screen patients for CI-AKI risk – history, blood results consider non-contrast scan, other tests minimise risk with prevention protocol HYDRATION is important role for contrast to renal function ratios?

Future Directions further investigation of the “safe” contrast dose does CI-AKI really exist? 3 recent high quality papers suggesting the relationship is coincidental rather than causal 15. McDonald R Radiology 2013 16. McDonald J Radiology 2013 17. McDonald J Radiology 2014

References RANZCR Guidelines for Iodinated Contrast Administration. March 2009, RANZCR Website. Hoste EA et al. Epidemiology of contrast-associated acute kidney injury in ICU patients: a retrospective cohort analysis. Intensive Care Med 2011; 37: 1921 – 31. Laskey WK et al. Volume-to-Creatinine Clearance Ratio. J Am Coll Cardiol 2007; 50: 584 – 90. Balemans CE et al. Epidemiology of contrast material-induced nephropathy in the era of hydration. Radiology 2012; 263: 706 - 13. Gurm HS et al. Renal Function-Based Contrast Dosing to Define Safe Limits of Radiographic Contrast Media in Patients Undergoing Percutaneous Coronary Interventions. J Am Coll Cardiol 2011; 58: 907 – 14. Adair W, Harris K, Entwisle J. Use of estimated eGFR values to identify patients at risk from iodinated contrast induces nephropathy. Clin Radiol 2006; 61: 714 – 715. SA Renal Network. Protocol For Prevention Of Contrast-induced Acute Kidney Injury, 2010. Sergie Z, Mehran R. NAC and CIN Prevention: Mounting Evidence of Inefficacy. Catheter Cardiovasc Interv 2012; 79: 927 – 8. Hiremath S, Brar SS. The evidence for sodium bicarbonate therapy for contrast-associated acute kidney injury: far from settled science. Nephrol Dial Transplant 2010; 25: 2802 – 4. Davenport MS et al. Contrast Material–induced Nephrotoxicity and Intravenous Low-Osmolality Iodinated Contrast Material: Risk Stratification by Using Estimated Glomerular Filtration Rate. Radiology 2013; 268: 719 – 728. Davenport MS et al. Contrast Medium–induced Nephrotoxicity Risk Assessment in Adult Inpatients: A Comparison of Serum Creatinine Level– and Estimated Glomerular Filtration Rate–based Screening Methods. Radiology 2013;269: 92 – 100. Nyman U et al. Contrast-Medium-Induced Nephropathy Correlated to the Ratio Between Dose in Gram Iodine and Estimated GFR in ml/min. Acta Radiol 2005; 46: 830 – 42. Altmann DB et al. Use of the Contrast Volume to Estimated Creatinine Clearance Ratio to Predict Renal Failure After Angiography. J Interven Cardiol 1997; 10: 113 – 9. Nyman U et al. Contrast Medium Dose-to-GFR Ratio: A Measure of Systemic Exposure to Predict Contrast-Induced Nephropathy after Percutaneous Coronary Intervention. Acta Radiol 2008; 49: 658 – 67. McDonald RJ et al. Intravenous Contrast Material–induced Nephropathy: Causal or Coincident Phenomenon? Radiology 2013; 267: 106 – 118. McDonald JS et al. Frequency of Acute Kidney Injury Following Intravenous Contrast Medium Administration: A Systematic Review and Meta-Analysis. Radiology 2013; 267: 119 – 128. McDonald JS et al. Risk of Intravenous Contrast Material–mediated Acute Kidney Injury: A Propensity Score–matched Study Stratified by Baseline-estimated Glomerular Filtration Rate. Radiology 2014; 271: 65 – 73.