Hydration for Contrast-Induced Acute Kidney Injury (CI-AKI) Prevention Wisit Cheungpasitporn August 8, 2014

Disclosure None

Definition and frequency of CI-AKI Lameire NH. Nephrol Dial Transplant. 2006 Jun;21(6):i11-23.

Definition in number of trials Numbers of trials in the literature using the following definitions of contrast-induced nephropathy: 0.5 mg/dL (44.2 mol/L) increase, 1.0 mg/dL (88.4 mol/L) increase, 25% increase, and 50% increase. Lameire NH. Nephrol Dial Transplant. 2006 Jun;21(6):i11-23.

CI-AKI: Definition An increase in SCr generally occurs within 3 days after contrast exposures (in a minority of cases, the peak increase of SCr may occur up until 5 days). Definition varies, increase in Cr of >25% from baseline and/or ≥0.5 mg/dL after 48 hrs is widely used in the literature. Individuals with increases of SCr compatible with the definition of AKI after administration of contrast media be also evaluated for other possible causes of AKI. KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012

CI-AKI: Incidence The reported incidence varies depending on risk factors, the amount and type of contrast, and the type of radiologic procedure. Among patients who have no risk factors, the risk of contrast nephropathy is negligible (ie, ≤1%). Among high risk patients (especially those with diabetes and CKD), the reported risk following percutaneous angiography with or without intervention is 10 to 20%. Solomon RJ et. al. Clin J Am Soc Nephrol 2009; 4:1162.

Factors involved in CI-AKI pathogenesis ?Not well understood Dangas G et al. Am J Cardiol. 2005;95:13-19.

Postulated Pathophysiology of CIN In the presence of a reduced nephron mass, the remaining nephrons are vulnerable to injury. Iodinated contrast, after causing a brief (minutes) period of vasodilation, causes sustained (hours to days) intrarenal vasoconstriction and ischemic injury. The ischemic injury sets off a cascade of events largely driven by oxidative injury causing death of renal tubular cells. If a sufficient mass of nephron units are affected, then a recognizable rise in serum creatinine will occur 8

Pathophysiology of CI-AKI Radiocontrast Administration Intrarenal Vasoconstriction ↓Blood flow Osmotic Load Generation of ROS Direct Cytotoxicity Medullary Hypoxia This slide depicts the principle processes involved in the pathogenesis of CIN. Specifically, it highlights the role of medullary hypoxia, direct cytotoxicity of radiocontrast, and the potntial role of free oxygen radicals. Poorly understood, complex syndrome, little known about underlying cellular mechanism Available contrast media constitute diverse family (ionic, nonionic, high/low/iso-osmolar) Biphasic response or immediate vasoconstriction (dose dependent) and reduction of renal blood flow (up to 50%, lasting for hours) Subsequent stasis of contrast causes direct tubular injury and death (osmotic nephrosis-intense focal or diffuse vacuolization of the proximal tubules- or overt tubular necrosis)) vasoconstriction through Ca influx causing regional cortico-medullary and outer medullary blood flow reduction CI-AKI Dangas G et al. Am J Cardiol. 2005;95:13-19.

Risk factors for CI-AKI Patient-related Renal insufficiency Diabetes mellitus Intravascular volume depletion Reduced cardiac output Concomitant nephrotoxins Procedure-related ↑ volume of radiocontrast Multiple procedures w/i 72 hours Intra-arterial administration Type of radiocontrast } additive risk This slide depicts the risk factors for CIN, highlighting the importance of underlying renal insufficiency, particularly in the setting of diabetes mellitus. McCullough PA et al. Am J Med. 1997;103:368-375.

Risk models McCullough et al. Am J Cardiol 2006

Mehran Risk Score for CIN post PCI . Mehran et al. JACC 2004 12

Weisbord SD et al. Clin J Am Soc Nephrol. 2013 Sep;8(9):1618-31.

Preventive strategies for CI-AKI Ineffective Unclear benefit Effective NAC Theophylline Aminophylline Ascorbic acid Statins Hemofiltration CCB Loop diuretics* Mannitol* Dopamine* Fenoldopam* ANP Hemodialysis* IVF Choice of contrast This slide depicts interventions that have been evaluated for the prevention of CIN. On the left side, are those measures that have been shown to be ineffective. Although some studies may have demonstrated a benefit to some of these interventions, the preponderance of evidence on these interventions suggest a lack of benefit, and in some cases harm. The middle column depicts interventions for which there is unclear benefit, and for which additional studies may help elucidate whether a benefit is present. The far right column depcict interventions that are effective – specifically, the use of iv fluids and using radiocontrast of low, and in the highest risk patients, iso-osmolarity. * Possibly harmful Weisbord SD et al. Clin J Am Soc Nephrol. 2013 Sep;8(9):1618-31.

Contrast Agents Name Type Iodine Content Osmolality Ionic Diatrizoate (Hypaque 50) Ionic Monomer 300 1550 High Osmolar Metrizoate (Isopaque Coronar 370) 370 2100 Ioxaglate (Hexabrix) Ionic dimer 320 580 Low Osmolar Non-Ionic Iopamidol (Isovue 370) Non-ionic monomer 796 Iohexal (Omnipaque 350) Non-ionic monomer 350 884 Iopromide Iodixanol (Visipaque 320) Non-ionic dimer 290 Iso Osmolar Pannu N et. al. JAMA 2006; 295:2765.

Clinical trials of volume expansion 1994 → present Provide clinical basis for: Protective effect of IVF Deleterious effect of furosemide Superiority of isotonic IVF Superiority of IVF to pt-directed oral fluids Potential benefit of oral NaCl This slide is a summary on the effect of iv fluids on reducing the incidence of CIN – see next slides for references

Rate of CIN: 11% 28% 40% RCT 78 patients This slide is from the Solomon study describing how the rate of CIN was lowest in patients who received just saline, higher in patients who received saline and mannitol, and highest in patients who received saline and lasix. This was the first clinical trial to look at the role of iv fluids and cin. 12 hour before and after. Chronic renal insuffiency Cr > 1.6, eGFR < 60 ml. inpatient+outpatient , mixed type of contrast Solomon R et al. N Engl J Med. 1994;331:1416-1420.

Isotonic v. hypotonic saline RCT 1,620 patients Isotonic v. hypotonic saline Elective+emergency PCI Low osmolar non-ionic contrast This study depicts how normal saline is more effective than half normal saline at preventing cin, with no effect on mortality or vascular complications. Normal renal function 67% of pts. Mueller C, et al. Arch Int Med. 2002; 162:329-336

Saline vs. Bicarbonate IV fluid RCT 119 patients Saline vs. Bicarbonate IV fluid (8/59) P = 0.02 (1/60) Result of the bicarbonate study showing lower rate of CIN with bicarbonate than saline a bolus of 3 mL/kg of isotonic bicarbonate for one hour prior to the procedure, and continued at a rate of 1 mL/kg per hour for six hours after the procedure. All procedures with contrast exposure Low osmolar non-ionic contrast Patients with Creatinine > 1.1 mg/dL Merten et al. JAMA 2004;291:2328-2334

Weisbord SD et al. Clin J Am Soc Nephrol. 2013 Sep;8(9):1618-31. a bolus of 3 mL/kg of isotonic bicarbonate for one hour prior to the procedure, and continued at a rate of 1 mL/kg per hour for six hours after the procedure. Weisbord SD et al. Clin J Am Soc Nephrol. 2013 Sep;8(9):1618-31.

Weisbord SD et al. Clin J Am Soc Nephrol. 2013 Sep;8(9):1618-31. A bolus of 3 mL/kg of isotonic bicarbonate for one hour prior to the procedure, and continued at a rate of 1 mL/kg per hour for six hours after the procedure. Weisbord SD et al. Clin J Am Soc Nephrol. 2013 Sep;8(9):1618-31.

KDIGO 2012: CI-AKI KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012

KDIGO 2012: CI-AKI KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012

Brar SS et. al. Lancet. 2014 May 24;383(9931):1814-23.

LEFT VENTRICULAR END DIASTOLIC PRESSURE ( LVEDP )

What does LVEDP mean anyway? LVEDP is the left ventricular end-diastolic pressure, and serves as a measure of the pre- load and thus that of circulating blood volume. Direct measurement of LVEDP is routinely performed during cardiac catheterization. Indirect measurement of the LVEDP by measuring the PAWP or pulmonary artery diastolic pressure measured with the balloon-tipped catheter. Kern MJ. The Cardiac Catheterization Handbook, 5th ed2011

Clinical Measurement of Preload LVEDP is measured just before the start of the systole ( i.e : End of the diastole ) LVEDP; normal = 4 - 12 mmHg Cardiogenic pulmonary edema: LVEDP ≥ 18 mmHg Kern MJ. The Cardiac Catheterization Handbook, 5th ed2011

Brar SS et. al. Lancet. 2014 May 24;383(9931):1814-23.

Objective To investigative different rates of fluid administration guided by the LVEDP to prevent CI-AKI in patients undergoing cardiac catheterization.

Participants Inclusion criteria Exclusion criteria No consent Emergency cardiac catheterization RRT Exposure to contrast within 2 days Contrast allergy Acute decompensated HF Severe valvular disease Mechanical aortic prosthesis LV thrombus Hx of kidney or heart Tx Change in eGFR ≥ 7.5%/d or a cumulative change ≥ 15% during the preceding 2 days ≤ GFR* 60 ml/min/1.73 m2 ≥ 18 years And at least one of the following DM CHF HTN Age ≥ 75 years * GFR was calculated using MDRD formula

Intervention – Fluid therapy 3 ml/kg in 1 hour before procedure Intra-arterial ioxilan (350 mg iodine/ml) Non-ionic, low – osmolar Fluid - NSS Measure LVEDP Randomization (1:1 ratio) LVEDP-guided hydration Standard hydration Prefer IV fluid in LVEDP group. Safe in IV fluid guided by LVEDP guided. Aggressive IV fluid. (selective aggressive fluid therapy) LVEDP < 13  5ml/kg/h 13-18  3ml/kg/h > 18  1.5 ml/kg/h 1.5 ml/kg/h Fluid started right before procedure and continued until 4 hours after procedure

Randomization and masking Stratified by DM status and NAC use NAC use 600 mg twice daily for 2 days Starting the day before index procedure Use was at the discretion of the physician. Permuted block sized of 4 Partly blinded Patient  masked Lab personnel  masked Physician  not masked

Outcomes Primary endpoint Secondary endpoint Safety endpoint ≥ 25% or 0.5 mg/dl increase in the SCr Only patients with ≥ 2 SCr values between day 1-4 were included Calculated with a baseline value obtained before procedure and the highest post-procedure value on days 1-4 Secondary endpoint Components of primary endpoint Occurrence of major adverse events A composite of all-cause mortality, MI, and RRT at 30 days and 6 months Safety endpoint Clinical sequelae of fluid administration and LVEDP measurement All adverse events were confirmed by personnel who were masked to treatment assignment Were included in primary analysis

Post-hoc analysis Rate of contrast-induced AKI Increase in SCr ≥ 0.3 mg/dl The frequency of persistent renal impairment ≥ 15% increase in SCr above baseline SCr samples were obtained 2-8 weeks after the index procedure and the 1st SCr value during this period was used in analysis

Statistical analysis Primary outcome Power calculation Relative risk, absolute risk reduction, number needed to treat Power calculation Superiority trial 18% in control group and 8% in LVEDP 390 patients needed for 80% power and a two-sided alpha of 0.05 Superiority trial 80% 390 patients

Outpatient/ambulatory procedure 58% overall 61% in LVDP-guided group 56% in control group P = 0.29 Outpatient 58%, not that sick

under 40% were women, and roughly half were diabetic, with a mean GFR of ~ 48mL/min/1.73m2

P < 0.001 1727 (583) 812 (142)

Incidence of contrast-induced AKI 11.4% The overall CI-AKI incidence was 11.4%, but with a striking difference of 16.3% in control versus 6.7% in the intervention arm - resulting in a RR of 0.41 with a NNT of only 11. Incidence of contrast-induced AKI 11.4% NNT = 11 for LVEDP-guided treatment

No significant interaction between treatment assignment by subgroup No differences were apparent in the different subgroups or different AKI measures studied (Tables 2 and 3). P value of difference in relative risk The benefit of LVEDP was similar No significant interaction between treatment assignment by subgroup

Result: contrast-induced AKI In patients GFR ≤ 45 ml/min/1.73 m2 Outcomes LVEDP –guided hydration Control RR (95% CI) P-value Contrast-induced AKI 5/60 (8%) 14/61 (23%) 0.36 (0.14-0.95) 0.03 NNT = 7 Benefit looks better in patients with GFR <45

Result: contrast-induced AKI LVEDP level LVEDP- guided Control RR (95% CI) P-value < 18 mmHg 8/152 (5.3%) 21/146 (14.4%) 0.37 (0.17-0.80) 0.008 ≥ 18 mmHg 4/26 (15.4%) 7/26 (26.9%) 0.57 (0.19-1.72) 0.31 Beware…. Not completely blind In >18 mmHg also decrease…although not significant

Result: contrast-induced AKI Increasing volume of NSS administered were associated with reduced rates of contrast-induced AKI OR = 0.91 (95% CI 0.89 – 0.94); P = 0.01 for every additional 100 ml of NSS administered Volume of NSS received Rate of contrast-induced AKI Tertile 1 (448-874 ml) 20/117 (17%) Tertile 2 (874-1512 ml) 13/117 (11%) Tertile 3 (1512-3055 ml) 7/116 (6%) P = 0.03 Confound that lower fluid…high LVEDP, sick, pulm edema

Result: persistent renal impairment Outcome LVEDP- guided Control RR (95% CI) P-value Persistent renal impairment 6/178 (3.4%) 12/172 (7.0%) 0.48 (0.19-1.26) 0.13 patients who developed contrast-induced AKI – persistent renal impairment occurred in 46% Outcome LVEDP- guided Control RR (95% CI) P-value Persistent renal impairment 6/12 (50%) 12/27 (44%) 1.13 (0.56-2.28) 0.75

NNT for LVEDP for prevention of one major adverse event at 6 mo = 16 Interestingly, the major adverse event rates (arguably comprising more important clinical outcomes)showed a similar beneficial trend, which was significant at 6 months. NNT for LVEDP for prevention of one major adverse event at 6 mo = 16

No contrast-induced AKI Result At 6 month Contrast-induced AKI No contrast-induced AKI RR (95% CI) P-value All-cause mortality higher 0.002 Myocardial infarction 0.02 Need for RRT <0.001 Cumulative major adverse event 10/40 (25%) 11/310 (3.5%) 7.1 (3.2-15.5)

Result- Safety 6 patients terminated the IV fluid early due to SOB 3 in LVEDP-guided  LVEDP 3, 7 and 26 mmHg 3 in control  LVEDP 3, 23 and 31 Hg No ventricular arrhythmias or other complication associated with LVEDP measurements reported Complication can occur in 3, 7…although with LVEDP

Result *adjusted for history of CHF and PCI status Outcome Risk ratio (95% CI) Contrast-induced AKI OR = 0.37 (0.18-0.74) Adjusted OR = 0.40 (0.19-0.81) Major adverse events at 6 months HR = 0.31 (0.13-0.78) Adjusted HR = 0.35 (0.14-0.89) *adjusted for history of CHF and PCI status Thus, the minor imbalances between treatment groups do not have a meaningful eff ect on the results. We investigated the eff ect of a dilutional eff ect of volume expansion on serum creatinine measurement and showed it to be negligible.

Discussion Pts with stable renal insufficiency undergoing cardiac catheterization and followed up for 6 months: LVEDP-guided fluid administration as compared with standard treatment resulted in 68% relative reduction in CI-AKI, and 59% relative reduction in major adverse clinical events.

Discussion LVEDP group was able to receive roughly twice the volume of NSS with a similar rate of fluid termination than the control group. Despite more IV fluid with LVEDP-guided therapy than with standard hydration, IV fluids were terminated at a similarly low rate in both study groups, which suggests that higher rates can be tolerated. The sustained administration of normal saline at 3 or 5 mL/ kg per h for at least 5 h are the highest hydration rates studied in a contrast-induced acute kidney injury prevention trial so far. Thus, despite more aggressive volume expansion with left ventricular enddiastolic pressure-guided therapy than with standard hydration treatment, intravenous fl uids were terminated at a similarly low rate in both study groups, which suggests that higher rates can be tolerated.

Discussion Pts with CI-AKI had a 7-fold increase in the rate of the composite major adverse events endpoint, and a significant increase in each of the components including death, MI, and RRT. These findings emphasize the importance of longer term follow-up in patients with CI-AKI. The study population was at a moderate to high risk of CI-AKI all patients had eGFR ≤ 60 mL/min/ 1.73 m2 and one additional CI-AKI risk factor The sustained administration of normal saline at 3 or 5 mL/ kg per h for at least 5 h are the highest hydration rates studied in a contrast-induced acute kidney injury prevention trial so far. Thus, despite more aggressive volume expansion with left ventricular enddiastolic pressure-guided therapy than with standard hydration treatment, intravenous fl uids were terminated at a similarly low rate in both study groups, which suggests that higher rates can be tolerated. All patients with new-onset dialysis during the follow-up period had previously developed CI-AKI after the index procedure.

Limitations The study was single-blinded (patients, and not investigators) which is understandable as the rate of fluid infusion would be difficult to mask. Patients with acute decompensated heart failure or severe valvular heart disease were excluded from the study. LVEDP assessment of intravascular volume status, it is only available in patients undergoing cardiac catheterization.

Conclusion IV NSS guided by LVEDP is well tolerated and could substantially reduce the incidence of CI- AKI and major adverse clinical events in patients undergoing cardiac catheterization. My Conclusion More IV fluid is better!!!

PRESERVE Contrast-induced AKI (CI-AKI) is a common condition associated with serious, adverse outcomes. CI-AKI may be preventable because its risk factors are well characterized and the timing of renal insult is commonly known in advance. Intravenous (IV) fluids and N-acetylcysteine (NAC) are two of the most widely studied preventive measures for CI-AKI. Despite a multitude of clinical trials and meta-analyses, the most effective type of IV fluid (sodium bicarbonate versus sodium chloride) and the benefit of NAC remain unclear. Careful review of published trials of these interventions reveals design limitations that contributed to their inconclusive findings. Such design limitations include the enrollment of small numbers of patients, increasing the risk for type I and type II statistical errors; the use of surrogate primary endpoints defined by small increments in serum creatinine, which are associated with, but not necessarily causally related to serious, adverse, patient-centered outcomes; and the inclusion of low-risk patients with intact baseline kidney function, yielding low event rates and reduced generalizability to a higher-risk population. The Prevention of Serious Adverse Events following Angiography (PRESERVE) trial is a randomized, double-blind, multicenter trial that will enroll 8680 high-risk patients undergoing coronary or noncoronary angiography to compare the effectiveness of IV isotonic sodium bicarbonate versus IV isotonic sodium chloride and oral NAC versus oral placebo for the prevention of serious, adverse outcomes associated with CI-AKI. This article discusses key methodological issues of past trials investigating IV fluids and NAC and how they informed the design of the PRESERVE trial. Weisbord SD et al. Clin J Am Soc Nephrol. 2013 Sep;8(9):1618-31.

Renal Guard™ Renal Guard therapy is designed to: Provide the benefits of hydration in an automatic system Prevent contrast agents from clogging in the kidney Limit toxin exposure in the kidneys Our therapy generates a high urine output while balancing the patient’s fluid input and output. Generating a high urine flow rate with the Renal Guard helps prevent the contrast agents from clogging in the kidneys and reduces the exposure of contrast toxins to the kidney. Renal Guard can be used during patient transport and throughout the catheterization process and recovery. Our proprietary single-use disposable set will include everything that must be used with each patient. Ultimately, the bottom line is that we believe Renal Guard can help prevent C-I-N. This C-I-N prevention is achieved while limiting the risk of over or under hydration; and we believe it will be easy enough to make available to a wide number of patients; and will reduce clinical time and effort. LA 00241 This presentation is the property of PLC Medical Systems, Inc.

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