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4/9/2018 Acute Kidney Injury: Ending learned helplessness John A. Kellum, MD, MCCM Professor of Critical Care Medicine, Medicine, Bioengineering and Clinical & Translational Science Vice Chair for Research Director, Center for Critical Care Nephrology Disclosures • Consulting: • • • • • • • • • • • • • Adrenomed AM Pharma Astellas Astute Medical Atox Bio Baxter Bioporto Cheetah Medical Cochlear Cytosorbents Eliaz Pharma Elsevier Grifols • • • • • • • • • • • • • • Grant support: Medibeacon MedScape Mitobridge Novartis NxStage PhotoPhage Potrero Premier Sirtex Sphingotech Sobi Spectral Diagnostics Venn Strategies • • • • • • • Astellas Astute Medical Bard Baxter Bioporto Grifols RenalSense • Intellectual Property: • Astute Medical • Cytosorbents • PhotoPhage Updated Jan 2018 AKI severity determines outcome Patients that recover do rather well Patients that don’t recover …do poorly Kellum et al. Am J Respir Crit Care Med. 2016 Feb 1;193(3):281-7. 1 4/9/2018 Differences in Fluid Administered PST EGDT Usual Care Renal Outcomes N Engl J Med 2014;370:1683-93. No treatment effect on… • RRT at any other time point or overall • New AKI or AKI progression (by KDIGO or Biomarkers) • AKI Recovery Kellum et al. Am J Respir Crit Care Med. 2016 Feb 1;193(3):281-7. 2 4/9/2018 AKI in Sepsis Sepsis/Septic Shock Immune response Pathogen Inflammation Coagulation LPS and other PAMPs Tissue Perfusion Cardiac Dysfunction O2 / Nutrients Systemic release: Mb, UA, HMGB1 Venous Congestion DAMPs 3 4/9/2018 NINJA NINJA UPMC 4 4/9/2018 Following First Dose of Vancomycin Ostermann et al. Crit Care Med. 2017 Nov 20. AKI No AKI • Avoid nephrotoxins (NSAIDs, ACEi/ARBs) • Avoid hyperglycemia • Optimize volume status and hemodynamics 5 4/9/2018 > 12 SVV Volume: crystallois 500-1000 ml ≤ 11 < 3l/min/m2 CI dobutamine or epinephrine > 3l/min/m2 MAP < 65 mmHg norepinephrine > 65 mmHg No Goal achieved Yes Check every 3h up to 12h after randomization Meersch et al. ICM 2017 Meersch et al. ICM 2017 Using biomarker enrichment the authors were able to achieve an effect with a number needed to treat of only 6. Without biomarkers it would have been >33. Nature Reviews Nephrology 2017 6 4/9/2018 UPMC AKI Alert Al-Jaghbeer M, et al. JASN 2017; Nov 2 Odds ratio 0.91, 0.86-0.96, P=0.001 Clinical Decision Support for Acute Kidney Injury and Hospital Survival METHODS OUTCOMES Outcomes were measured pre- and postimplementation of a Clinical Decision Support System (CDSS) for AKI Outcomes Pre- and Post-CDSS 40% implementation 12 Pre-CDSS (12 months): []% 10 []% [] [].0 6.7% 8 181k patients 11.0% clinically diagnosed AKI [] 6 4 2 [] [].0% []% []% 0 Mortality Implemented the CDSS LOS in days Mortality* LOS in days* No AKI • • Pre CDSS Derives reference serum creatinine from historical values in EMR Flags creatinine changes and KDIGO stage RRT* AKI Clinical Decision Support System *P<.001 Post CDSS CONCLUSION Implementation of a CDSS for AKI resulted in a small but sustained decrease in hospital mortality, length of stay and use of dialysis. Post-CDSS (24 months): 346k patients 12.8% clinically diagnosed AKI doi: 10.1681/ASN. 20 18 16 14 12 10 8 6 5.6% 4.7% 4 P=0.01 2 0 Balanced Saline 2x Creatinine RRT Death N = 13,347 15.4% 14.3% P=0.04 Balanced Saline 2x Creatinine RRT Death N = 15,802 7 4/9/2018 What's in the IV bag? Studies show safer option than saline •BY MARILYNN MARCHIONE, AP CHIEF MEDICAL WRITER Feb 27, 2018, 5:10 PM ET Conclusions • Markers of cell-cycle arrest appear to be robust measures of risk for AKI (manifesting in the next 12-24h) • Underlying biology suggestive of an “alarm-phase” marker before actual damage has a occurred. • A “KDIGO Bundle” can reduce AKI when applied to biomarker positive patients after cardiac surgery. • Nephrotoxic drug exposure accounts for as much as 30% of AKI and may contribute to more than half. • Improved risk assessment and early detection can prevent Acute Renal Failure. • Stop using saline! Follow @CCCNPitt www.ccm.pitt.edu 8 4/9/2018 ACUTE KIDNEY INJURY (AKI) TREATMENT AND MANAGEMENT PREVENTING AKI INDUCED ADVERSE DRUG EVENTS SANDRA KANE-GILL, PHARMD, M SC, FCCM, FCCP A SSOCIATE PROFESSOR, UNIVERSITY OF PITTSBURGH CRITICAL CARE M EDICATION SAFETY PHARMACIST, UPMC FACULTY, CENTER FOR CRITICAL NEPHROLOGY, UPMC AND UNIVERSITY OF PITTSBURGH CONFLICT OF INTEREST • NO DISCLOSURES PREVALENCE OF DRUG ASSOCIATED ACUTE KIDNEY INJURY (D-AKI) IN THE ICU • 5,143 PATIENTS IN 20 ICU S • 20% (74/355) ASSOCIATED WITH • ICU S AT 5 HOSPITALS DRUGS 3rd-5th • 25% (157/618) ASSOCIATED WITH DRUGS • 26,269 CRITICALLY ILL PATIENTS IN 54 HOSPITALS IN 23 COUNTRIES • 19% (328/1726) ASSOCIATED WITH DRUGS Brivet FG et al. Crit Care Med 1996;24:192; Mehta RL et al. Kid International 2004;66:1613-1621; Uchino S et al. JAMA 2005;294:813-818. 1 4/9/2018 D-AKI CONSEQUENCES PEDIATRIC, NON-ICU PATIENTS Variable AKI due to Nephrotoxin (n=77) No AKI P Value Baseline eGFR (mL/min/1.73m2) 118 120 0.48 eGFR at 6 months (mL/min/1.73m2) 113.8 123.4 0.04 Up/C ratio at 6 months, mg/mg 0.9 .0.27 0.04 Hypertension 37.7% 19.3% 0.01 ≥ 1 sign of CKD 33.7% 8.8% <0.01 • 70% of patients with drug associated AKI have evidence (reduced eGFR, hyperfiltration, proteinuria, or hypertension) of residual kidney damage Menon S et al. J Pediatr 2014;165:522 D-AKI CONSEQUENCES 60% 50% 30% Acute Tubular Necrosis (ATN) Nephrotoxicity 20% ATN + Nephrotoxicity 40% 10% Other Etiologies 0% In-Hospital Mortality In-Hospital Mortality and/or Dialysis Dependence Similar, slightly better, mortality rates and/or dialysis dependence compare to AKI of other etiologies Mehta RL et al. Kid Int 2004;66:1613 TRANSITIONING FROM ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE • PATIENTS WITH AKI HAVE A SUBSTANTIAL RISK OF PROGRESSING TO CKD • ABOUT 30% OF PATIENTS WHO HAVE AKI PROGRESS TO CKD • DIALYSIS DEPENDENCE FOR AKI SURVIVORS IS 40% Chawla LS et al. Nat Rev Nephrol 2017;13:241. AKI- acute kidney injury AKD- acute kidney disease CKD- chronic kidney disease 2 4/9/2018 RISK FACTORS FOR AKI/D-AKI Description Risk Factors for Critically Ill Susceptibilities Age, black race, female, history of diabetes, history of hypertension, previous AKI episode, elevated baseline serum creatinine Exposures Nephtoroxin administration, trauma, burn, circulatory shock, sepsis, high risk surgery, hypotension, fluid overload Drug-specific Exposure Nephrotoxin treatment duration, cumulative dose, total daily dose, pharmacokinetic and pharmacodynamic drug interactions, nephrotoxic burden Kane-Gill SL, Goldstein SL. Crit Care Clin 2015;31:675 Cotner SE et al. AAC 2017;61:e00871 Cartin-Ceba R et al. Crit Care Res Pract 2012; article ID 691013 Ostermann M et al. Crit Care Med 2018: ahead of print ▪ Concomitant nephrotoxin administration was an independent predictor of AKI ▪ 53% greater odds of developing AKI for every nephrotoxic drug received (OR 1.53; CI 1.09-2.14) ▪ Significant association between cumulative number of exposures and risk of AKI (p = 0.02) but no association between the each type of exposure and AKI (p = 0.22 ) ADVANCE OUR THINKING BEYOND SINGLE NEPHROTOXINS: DRUG COMBINATIONS • EVIDENCE FOR DRUG CLASS COM BINATIONS ASSOCIATED WITH AKI • COM PLETED A FORM AL GRADE PROCESS FOR QUALITY OF EVIDENCE ASSESSM ENT • 76 UNIQUE DRUG COM BINATIONS • 74% VERY LOW QUALITY OF EVIDENCE (D) • 16% LOW QUALITY OF EVIDENCE (C) • 10% MODERATE QUALITY OF EVIDENCE (B) • 0% HIGH QUALITY OF EVIDENCE (A) Rivosecchi RM et al. Ann Pharmacother 2016;50:953-972. DRUG COMBINATIONS: MODERATE QUALITY OF EVIDENCE Drug Class 1 Drug Class II Mechanism NSAIDs Diuretic pharmacodynamic effect with a decrease in prostaglandin synthesis by NSAIDs causing afferent vasoconstriction and a decrease in effective blood volume by diuretics NSAIDs Diuretic plus reninangiotensin aldosterone system “triple whammy” cumulative pharmacodynamic effect of each drug - exacerbated by the efferent arteriolar vasodilation caused by the RAAS Statins Macrolide increased serum statin concentrations as a result of inhibition of the cytochrome 450 (CYP450) enzyme system by macrolides Calcium channel blockers Clarithromycin CYP3A4 inhibition of clarithromycin, leading to elevated concentrations of calcium channel blockers leads to global hypotension, affecting the kidney results in ischemic renal injury resulting in AKI Statins Calcium channel blockers drug-drug interaction between certain calcium channel blockers inhibiting CYP3A4 metabolism of statins metabolized through this pathway Piperacillin/tazobactam Vancomycin decreased vancomycin clearance caused by piperacillin/tazobactam potentially leading to a greater degree of vancomycin exposure Rivosecchi RM et al. Ann Pharmacother 2016;50:953-972. 3 4/9/2018 PREVENTING AKI INDUCED ADVERSE DRUG EVENTS EARLY WARNING AND HYPERVIGILANCE KINETICS OF URINARY BIOMARKERS(KIM-1, NGAL) AND VANCOMYCIN EXPOSURE AUC-ROC 95% CI SCr Day 0 0.447 0.222-0.673 SCr Day 1 Biomarker 0.676 0.461-0.892 SCr Day 2 0.782 0.582- 0.981 SCr Day 3 0.799 0.617- 0.981 uKIM-1 Day 0 0.769 0.629-0.910 uKIM-1 Day 1 0.724 0.556-0.892 uKIM-1 Day 2 0.849 0.75-0.948 uKIM-1 Day3 0.781 0.658-0.904 uNGAL Day 0 0.703 0.575-0.831 uNGAL Day 1 0.733 uNGAL Day 2 0.824 0.7260.922 uNGAL Day 3 0.812 0.698-0.927 uKIM-1 and uNGAL 0.852 0.754-0.996 NGAL = Neutrophil gelatinase-associated lipocalin; KIM-1 = kidney injury molecule-; AUC-ROC= area under the receiver operating characteristic curve 0.59-0.877 Pang HM et al. Eur Rev Med Pharmaocol SCI 2017;21:4203 BIOMARKER(TIMP2-IGFBP7)KINETICS AND VANCOMYCIN EXPOSURE Ostermann M et al. Crit Care Med 2018: epub ahead of print 4 4/9/2018 HYPERVIGILANCE/SURVEILLANCE PREVENTION IN PEDIATRIC, NON-ICU PATIENTS • DEVELOPMENT AND REFINEMENT OF A PREDICTIVE AKI TRIGGER WITH THE GOAL OF REDUCING AKI SEVERITY • KNOWLEDGE FOR ALERT • ≥3 NEPHROTOXINS ON THE SAME DAY • IV AMINOGLYCOSIDE FOR ≥ 3 DAYS • RECENT: VANCOMYCIN FOR ≥ 3 DAYS • PHARMACIST MANAGED ALERT -OUTSIDE OF WORKFLOW AND ADVICE PROVIDED TO PRACTITIONER • EVIDENCE OF AKI • PEDIATRIC RIFLE CRITERIA; NO URINE EVALUATION • RISK: ECRCL DECREASE BY 25% • I NJURY: ECRCL DECREASE BY 50% • FAILURE: ECRCL DECREASE BY 75% • 1-YR: 42% DECREASE IN AKI INTENSITY WITH A REDUCTION IN DAYS IN AKI PER 100 EXPOSURE DAYS • 3-YR: RESULTS SUSTAINED WITH A 31% AKI INTENSITY DECREASE AND A 64% AKI RATE DECREASE Goldstein SL et al. Pediat rics 2013;132:e756 Kirkendall ES et al. Appl Clin Inform 2014;5:313 Goldstien SL Kidney Int 2016;90:212 CHANGE SERUM CREATININE TO BIOMARKER MONITORING • ADULTS? ICU PATIENTS? • W E ALREADY MONITOR SERUM Alert ≥3 nephrotoxins Pharmacists evaluate alert -repeat, patient already has AKI CREATININE REGULARLY Pharmacists aid in interpretation and makes medication management recommendations Pharmacists order biomarker test and inform physician QI- evaluate medication recommendations made, AKI severity , days of AKI and AKI incidence Frazee E, Voils S, Kane-Gill SL. Pharmacotherapy (in press). 30000 25000 20000 15000 10000 5000 0 AKIN 3 dialysis AKIN 2 AKIN 1 Cost of AKI in CTICU patients Total Costs AKIN 3 no… $60,000 $50,000 $40,000 $30,000 $20,000 $10,000 $0 No AKI COST OF AKI Increment al Costs BigpAK - One ICU day LOS reduction in intervention about a $2400 (US) savings Averting or reducing AKI severity in one patient could result in cost savings. Budget impact models and economic evaluations are needed Dasta JF et al. Nephrol Dial Transplant 2008;23:1970-4 Collister D et al. Clin J Am Soc Nephrol 2017: 12:1733 Gocze I et al. Annals of Surgery 2017; epub ahead of print 5 4/9/2018 ACUTE KIDNEY INJURY (AKI) TREATMENT AND MANAGEMENT PREVENTING AKI INDUCED ADVERSE DRUG EVENTS SANDRA KANE-GILL, PHARMD, M SC, FCCM, FCCP A SSOCIATE PROFESSOR, UNIVERSITY OF PITTSBURGH CRITICAL CARE M EDICATION SAFETY PHARMACIST, UPMC FACULTY, CENTER FOR CRITICAL NEPHROLOGY, UPMC AND UNIVERSITY OF PITTSBURGH Disclosures: None 6 4/16/2018 Case of Acute Kidney Injury • John Videen, M.D. • Nephrologist with Balboa Nephrology Medical Group • Sharp Chula Vista Medical Center Disclosures • Speaker for Astute Medical • Speaker for Merck Pharmaceuticals Case of Acute Kidney Injury • 60 year old male, with massive obesity, chronic obstructive pulmonary disease and worsening bilateral lower extremity edema admitted with cellulitis of the legs. • He had recurrent cellulitis and previous skin grafts of this region. • Comorbidities of obstructive sleep apnea, atrial fibrillation and schizophrenia. • Frequently admitted with respiratory issues, poorly compliant. 1 4/16/2018 Case of Acute Kidney Injury Initial Evaluation • HR 120, irregular, 119/60, T 38.5 • Weight estimated at 500 lb. Edema noted from feet to abdomen several mm in depth, large pannus, chronic hyperkeratotic lesions of legs, with lipodermatosclerosis. Draining open wounds. Awake and alert. • MRSA nasal screen +, wbc 16k, Crn 0.9. Bicarbonate 34. • CXR showed layering effusions. Case of Acute Kidney Injury Initial Therapy • Treated with vancomycin, receiving 7 gm over the first 48 hr and piperacillin-tazobactam. • Diuretics started: bumetanide 1 mg IV bid plus spironolactone 25 mg bid. • Urine output was about 200 ml over 8 hr. • Complained of pain, demanding treatment with narcotics. Case of Acute Kidney Injury Deterioration • Late on day 2 he became drowsy, not responding to naloxone or bipap. • Episodes of bradycardia noted. • Transferred to the ICU. • ABG: 7.09/pCO2 118/pO2 124 • Intubated with bronchoscopy showing clear airways. Hemodynamics stabilized with pressors. HR 110s. • Crn rose to 1.4 on day 3. • Foley placed with urine output <10 ml/hr • Biomarker TIMP2*IGFB7 measured >10 2 4/16/2018 Case of Acute Kidney Injury ICU Treatment • Blood cultures remained negative. Streptococcus grew from wound and vancomycin was stopped. Cephalosporin given. • Bumetanide increased to an intravenous infusion at 1 mg/hr. • Urine output improved to 150 ml/hr over 12 hr. • Metolazone 10 mg given PO. Case of Acute Kidney Injury Resolution • UO increased to 800 ml/hr and diuretics stopped and a spontaneous diuresis continued. • Creatinine peaked at 2.1, returned to baseline over next 2 weeks. • Tracheostomy performed. • Transferred to lower level of care. Case of Acute Kidney Injury Teaching Points • Not a single insult to the kidney • Despite co-morbidities, his renal function was normal before admission. • Period of hemodynamic instability. • Exposed to nephrotoxic agents: Vancomycin and Piperacillin-Tazobactam. • Elevated renal vein pressure. 3 4/16/2018 Heart Failure Forward Heart Failure Backward Heart Failure Renal Venous Congestion Oliguric Renal Failure Activation: Sympathetic NS Renin/Angiotensin ADH Sodium Retention Intrinsic Renal Disease That’s all folks, Any Questions? 4
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