Non-pharmacological Strategies to Prevent Kidney Injury in Patients Undergoing Contrast Media Exposure Eugenia Nikolsky, MD, PhD, FACC, FESC

Transcription

1 Non-pharmacological Strategies to Prevent Kidney Injury in Patients Undergoing Contrast Media Exposure Eugenia Nikolsky, MD, PhD, FACC, FESC Rambam Health Care Campus Technion - Israel Institute of Technology

2 I, Eugenia Nikolsky, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

3 Background Acute kidney injury is a strong predictor of increased short- and long-term mortality in patients undergoing contrast media exposure. Chronic renal insufficiency, diabetes mellitus and older age are the main factors in the development of AKI. Even small decline in renal function is strongly linked to worse prognosis.

4 Mortality Associated with Changes in Serum Creatinine n=9,210 hospitalized adult patients with consecutive SCr values Criterion Unadjusted OR (95% CI) Age-and gender-adjusted OR (95% CI) Multivariable OR (95%CI) Area under ROC Curve SCr>0.3mg/dl 6.9 (5.2 to 9.0) 6.6 (5.0 to 8.7) 4.1 (3.1 to 5.5) 0.84 SCr>0.5mg/dl 11.1 (8.7 to 14.2) 10.6 (8.3 to 13.6) 6.5 (5.0 to 8.5) 0.86 SCr>1.0mg/dl 19.9 (15.1 to 26.1) 19.0 (14.4 to 25.0) 9.7 (7.1 to 13.2) 0.84 SCr>2.0mg/dl 36.4 (24.3 to 54.6) 37.7 (25.0 to 56.9) 16.4 (10.3 to 26.0) 0.83 SCr by 25% 4.0 (3.0 to 5.2) 3.9 (3.0 to 5.2) 2.0 (1.2 to 3.9) 0.83 SCr by 50% 5.9 (4.6 to 7.5) 5.8 (4.6 to 7.5) 4.4 (3.4 to 5.7) 0.84 SCr by 100% 8.9 (6.9 to 11.4) 9.2 (7.1 to 11.8) 6.5 (4.9 to 8.6) 0.84 SCr by 50% to a minimum peak of 2.0 mg/dl 16.9 (12.8 to 22.3) 15.9 (12.0 to 21.0) 7.9 (5.8 to 10.9) 0.84 SCr>0.5mg/dl with baseline SCr<2.0 mg/dl or SCr>1.0 mg/dl with baseline SCr >2.0 and<5.0 mg/dl 11.0 (8.6 to 14.0) 10.5 (8.2 to 13.4) 6.5 (5.0 to 8.5) 0.84 Chertow GM et al. J Am Soc Nephrol 2005;16:

5 Pharmacological Therapies in the Prevention of CI-AKI Treatment Effect Hydration + Prostaglandin E 1 + Sodium bicarbonate +/ N-acetyl-l-cysteine +/ Dopamine +/ Fenoldopam +/ Theophylline +/ Calcium channel blockers +/ Atrial natriuretic peptide (+) positive effect ( ) no effect (+/ ) conflicting data

6 Non-pharmacological Strategies to Prevent CI-AKI Periprocedural RRT Hemodialysis Hemofiltration Contrast removal during the procedure Contrast volume reduction Systemic hypothermia Ischemic preconditioning Forced diuresis with RenalGuard

7 Prophylactic Hemodialysis Study Patients # Baseline SCr, Timing of hemodialysis post procedure Outcome Lehnert et al 1 30 Mean: 2.4 mg/dl Mean: 63.6 min HD group: 53% Control: 40% NS difference Vogt et al >2.26 mg/dl Range: min NS difference in SCr raise; more recurrent HD in the HD group Frank et al 3 17 >3.0 mg/dl 4-hour on-line NS difference in SCr change Lee et al 4 82 >3.5 mg/dl NA Less raise in SCr in HD group and less HD at FU 1 Nephrol Dial Transplant 1998;13: Am J Med. 2001; 111: Clin. Nephrol 2003;60: JACC 2007; 50:

8 Prophylactic Hemodialysis in Prevention of CI-AKI Design DESIGN: Prospective, openlabeled, randomized trial A total of 82 patients with CRI (SCr > 3.5 mg/dl) undergoing elective coronary interventions at Kaohsiung Veterans General Hospital in Taiwan from 2001 to 2006 Randomization OBJECTIVE: to investigate the role of prophylactic hemodialysis, as compared with isotonic-saline hydration, in preventing CIN in patients with renal failure Normal saline IV 1 ml/kg/h for 6 h before and 12 h after contrast medium exposure and hemodialysis asap post procedure N=42 Normal saline IV 1 ml/kg/h for 6 h before and 12 h after contrast medium exposure N=40 Primary endpoint: the change in CrCl between baseline and the 4 th day. Lee PT et al, JACC 2007; 50:

9 ml/min/1.73 m2 % Prophylactic Hemodialysis to Prevent CI-AKI Change in CrCl between day 0 and 4: -0.4 P= Hemodialysis Control Need in long-term dialysis: P= Lee PT et al, JACC 2007; 50:

10 Hemofiltration to Prevent CI-AKI Design DESIGN: Prospective, openlabeled, randomized trial 114 consecutive patients with CRI (SCr >2 mg/dl) undergoing elective coronary interventions at Centro Cardiologico Monzino in Milan from 2000 to 2001 Randomization OBJECTIVE: to investigate the role of hemofiltration, as compared with isotonicsaline hydration, in preventing CIN in patients with severe renal failure Hemofiltration 1000 ml/hr without weight loss in ICU 4 to 8 hours before intervention and for 18 to 24 hours post intervention N=58 Isotonic-saline hydration 1 ml/kg /hr 4 to 8 hours before intervention and for 18 to 24 hours post intervention N=56 Primary endpoint: Change in SCr and in-hospital mortality Marenzi G et al, N Engl J Med. 2003;349:

11 Hemofiltration to Prevent CI-AKI Marenzi G et al, N Engl J Med. 2003;349:

12 % Hemofiltration to Prevent CI-AKI Hydration P= In-hospital mortality Hemofiltration 30 P= year mortality Drawbacks: Need in ICU bed High cost Marenzi G et al, N Engl J Med. 2003;349:

13 CS Aspiration System and Renoprotective Effect Interface Unit Support Device Tubing Set Pressure Transducer CINCOR Contrast Removal System, Osprey Medical, St. Paul, MN Duffy et al. JACC 2010;6:525-30

14 CS Aspiration System and Renoprotective Effect Baseline 72 hrs post procedure Successful CS cannulation: 76% Mean time: 11 min No SAEs Recapture of 32% of CM (Range: 6% to 64%) Mean volume of aspirated blood: 170 ml Mean Hgb drop: 0.5 mg/dl N=148 patients N=26 patients Duffy et al. JACC 2010;6:525-30

15 The AVERT Contrast Modulation System The technology attaches to the manifold setup & provides an adjustable resistance circuit which decreases the pressure head delivering contrast toward the patient. This action results in less contrast volume delivered over time compared to conventional manifold injections.

16 AVERT Trail Results Summary N=578 pts at 37 US sites, enrollment completed in July 2015

17 BRIEF ISCHEMIA AT REMOTE ORGAN Communication pathways Key molecular mediators Humoral Adenosine Bradykinin Opioids Erythropoietin CGRP Angiotensin I Neuronal Adenosine Bradykinin CGPR Systemic Anti-inflammatory Anti-apoptotic Anti-oxidant inos HSP COX2 Protein kinases PKC, PKG MAPK, MEK Erk ½, Akt cgmp-dependent-kinase JAK Mitochondria KA ATP channel opening mptp inhibition ORGAN PROTECTION Transcription factors STAT 1/3 NFxB AP-1 Nrf2 HIF-1a Gassanov et al. JASN 2014;25:216-24

18 Ischemic Preconditioning for Prevention of CI-AKI Renal Protection (RenPro) Trial 267 consecutive patients 100 patients with egfr<60 randomly assigned to treatment in a 1:1 ratio 167 excluded because did not meet study criteria 153 without renal impairment 6 on chronic hemodialysis program 8 did not agree 50 patients received standard coronary angiography plus ischemic preconditioning (intervention (IPC) group) 50 patients received standard coronary angiography plus sham ischemic preconditioning (control group) 50 patients eligible for inclusion in data analysis for CI-AKI (intention-to-treat analysis) 50 patients eligible for inclusion in data analysis for CI-AKI (intention-to-treat analysis) 9 lost for 6-weeks follow-up 9 underwent major cardiac surgery 10 lost for 6-weeks follow-up 9 underwent major cardiac surgery 1 received repeat angiography 41 patients completed follow-up with data 40 patients completed follow-up with data Er et al. Circulation.2012;126:

19 Ischemic Preconditioning: Protocol IPC group: 4 cycles of alternating 5-min inflation and 5-min deflation of a standard upper-arm BP cuff to the individual s systolic BP +50 mm Hg. IPC was started immediately before CA. The mean time between the last inflation cycle and the start of CA: 45 min. Control group: sham preconditioning in the same way as IPC, by inflating an upper-arm blood pressure cuff to diastolic pressure levels and then deflating the cuff for 10 mm Hg to maintain non-ischemic upper-arm compression. Investigators blinded to the assignment.

20 RenPro Trial Outcomes 1 Endpoint: Rates of CI-AKI 40% 47% 37% 12% 12% 0% Er et al. Circulation.2012;126:

21 Level of Urinary NGAL (%) RenPro Trial: Surrogate Measures for AKI Er et al. Circulation.2012;126:

22 COOL RCN Randomized Trial Pts at risk for RCN (CrCl ml/min) Undergoing diagnostic and/or interventional cath with >50 cc dye N = 400 pts at up to 35 sites R Hypothermia (33-34 C) Pre contrast and 3 hrs post + Hydration (NaCl & NaHCO3 ) Control Hydration (NaCl & NaHCO3 ) SCr measured at 24, 48 and hrs* (core lab) 1º efficacy endpoint = RCN (SCr >25% from baseline) 1º safety endpoint = 30d AE (death, MI, dialysis, VF, venous compl requiring surgery, bleed requiring 2U transf., rehosp.) Stone GW et al. Am J Cardiol 2011;108:741-6

23 Cooling Procedures Cooling must be achieved before 1 st contrast Target core temp 33ºC Shivering suppression protocol (45-60 pre cool): o o o Buspirone 60 mg po Meperidine 50 mg slow IV bolus; 15 later mg slow IV bolus; 15 later start mg/hr IV infusion Surface forced air warming blanket (at high) Rewarming initiated 3 hours post procedure towards a target of 36ºC at a rate of 1 C/hr Stone GW et al. Am J Cardiol 2011;108:741-6

24 Patients (%) Development of RCN 30 Normothermia (n=70) Hyporthermia (n=58) OR [95%CI] = 1.27 [ ] P=0.59 OR [95%CI] = 0.83 [ ] P=0.69 OR [95%CI] = 1.16 [ ] P=0.71 Relative>25% Absolute>0.5 mg/dl Absolute or relative Stone GW et al. Am J Cardiol 2011;108:741-6

25 RenalGuard for AKI Prevention: Mechanism of Action Flush CM out of kidneys Reduces Oxidative stress Promote and monitor urine output Creates and maintains high urine flow rates Rapidly clears renal toxins Prevents contrast from clogging tubules Avoids injury to kidneys High urine flow rates make the kidney work less Lowers kidneys oxygen requirement Less damage from low blood flow Less oxidative stress

26 Forced Diuresis A high volume (~1 L/hr) of controlled hydration is required in high-risk patients This goal can be achieved by exactly matching IV hydration to furosemide-induced high-volume diuresis to avoid hypovolemia (RenalGuard system)

27 RenalGuard System RenalGuard System is designed to: o Automatically match IV fluid replacement to urine volume in real-time during furosemide-induced forced diuresis This treatment may: o Reduce the risk of over- or underhydration o Dilute contrast agent in the renal tubules o Limit kidneys exposure to contrast agent RenalGuard System - PLC Medical Systems, Inc, Milford, MA

28 RenalGuard System High-volume fluid pump Weight measuring system IV set Urine collector connected to Foley catheter Real time display of urine & fluid replacement Alerts for fluid bag & urine replacement

29 MYTHOS Trial: RenalGuard vs. Controls Cumulative IV saline Urine output Treatment period RenalGuard hrs Controls hrs A 2-fold higher IV hydration rate and a higher urine output were obtained *Matched in a 4-fold to the shorter infusion time rate in (minus RenaGuard the initial treated 250 patients ml saline as bolus) compared to controls Marenzi G et al, J Am Coll Cardiol Intv 2012;5:90-7

30 ml Average Urine Rate and Fluid Infusion After RenalGuard Start Avrg Urine Rate Avrg Infusion Rate Time since RG (h:mm) Dorval JF et al, Int J Cardiol.

31 Study RenalGuard Clinical Data Review Control Lasix Dose (mg/kg) N Result P US Pilot None Safety only n/a MYTHOS REMEDIAL II AKIGUARD Overnight Hydration Sodium Bicarbonate Overnight Hydration RenalGuard RenalGuard RenalGuard 0.02 PROTECT-TAVI Hydration RenalGuard US Pivotal Saline Hydration Ongoing -

32 European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Guidelines: Recommendations for prevention of CI-AKI Recommendations Dose Class a Level b Ref c Patients with moderate-to-severe CKD Furosemide with matched hydration may be considered over standard hydration in patients at very high risk for CIN or in cases where prophylactic hydration before the procedure cannot be accomplished. Initial 250ml intravenous bolus of normal saline over 30 min (reduced to 150 ml in case of LV dysfunction) followed by an i.v. Bolus ( mg/kg) of furosemide. Hydration infusion rate has to be adjusted to replace the patient s urine output. When the rate of urine output is >300 ml/h, patients undergo the coronary procedure. Matched fluid replacement maintained during the procedure and for 4 hours post-treatment. llb A

33 European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Guidelines: Recommendations for prevention of CI-AKI Windecker S, et al ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J

34 Conclusions The results of several new non-pharmacological strategies to prevent AKI in patients undergoing CM exposure are promising but should be explored in larger randomized trials. The use of RenalGuard allows to reduce significantly rates of CI-AKI in moderate-to-high patients. Hemofiltration should be considered in patients at very high risk of CI-AKI.