AKIN Criteria for Diagnosis of AKI

Transcription

1 Acute Kidney Injury (AKI): Definition and Diagnostic Criteria Formerly referred as acute renal failure Antimicrobial Safety: Spare the Kidneys Annie Wong-Beringer, Pharm.D., FIDSA Over 30 definitions for ARF used in literature 25% over baseline Scr to need for dialysis Difficultto to standardize care and design preventive and treatment strategies AKI complex disorder reflecting the entire spectrum of ARF An acute decline in kidney function secondary to an injury that causes functional and structural changes in the kidneys. Consensus development from the ADQI (major critical care and nephrology societies worldwide) for uniform standards for definition and classification of AKI RIFLE and AKIN criteria Disclosure AKIN Criteria for Diagnosis of AKI Annie Wong-Beringer reports the following relevant financial relationships: Research Grant Recipient: Pfizer Inc., Forest Inc. Ricci, Nat Rev Nephrol 2011 Learning Objectives Pathophysiology of AKI 1. Discuss the diagnosis, epidemiology, and pathophysiology of acute kidney injury (AKI). 2. Identify predisposing risk factors for antibiotic associated AKI High dose vancomycin Telavancin Colistin 3. Evaluate a monitoring plan to facilitate early detection of AKI. KIM 1 4. Develop an alternative treatment plan in the event AKI develops. Vaidya, Annu Rev Pharmacol Tox 2008 Page 1 of 8

2 Epidemiology of AKI AKI complicates 1% to 7% of all hospital admissions. ICU patients 20 30% develop AKI % mortality rate. 13% remained dialysis dependent for those who survived to hospital discharge. Nephrotoxic drugs contributing factors in 19 25% of cases of severe AKI. Pannu, Crit Care Med 2008 Vaidya, Annu Rev Pharmacol Toxicol 2008 Vancomycin Associated Nephrotoxicity (NT) Increasing reports of NT with high dose therapy. Uncommon at standard dose (Rybak, 1990) 5% vanco vs 11% AG vs 22% vanc + AG Risk factors: concomitant nephrotoxin, Tr > 10mg/L, prolonged duration (>21 d) Pathogenesis Dose and time dependent exposure causes proximal tubule necrosis and mitochondrial damage involving oxidative stress and potentially inflammation and complement activation. Dieterich, Tox Sci 2009 Arimura, Free Rad Biol Med 2012 Current Practice Management of infections caused by antibioticresistant pathogens have necessitated the use of more aggressive dosing or renal toxic antibiotics: High dose vancomycin (Trough mg/l) Telavancin Colistin (or polymixin) Review of Literature Majority of studies were retrospective in design Study definitions used (most common): High dose (HD): Tr 15 20mg/L or 4g/d NT: 50% in Scr over baseline or 50% in Clcr from baseline on2 consecutive measurements. Study population, total adults treated >2,000 Age range: 55 65y in most studies; mean range 6 74y HD (n > 485) vs SD (n > 1174) Most received concomitant nephrotoxins; subgroup analysis on those without Wong Beringer, Int J Antimicrob Agents 2011 High Dose Vancomycin Therapy Reports of treatment failure of MRSA strains with high vancomycin MIC in susceptible range. High Dose recommended for complicated infections: trough ug/ml and/or AUC:MIC 400 ATS 2005 for MRSA pneumonia ASHP IDSA SIDP 2009 for bacteremia, endocarditis, osteomyelitis, meningitis, hosp acquired pneumonia by Staph aureus IDSA 2011 Guidelines for serious MRSA infections AJRCCM 2005; Rybak et al. AJHP 2009; Clin Infect Dis 2011 Duration of Exposure Risks for Developing NT with High Dose Vancomycin Therapy Age, APACHE II, ICU stay NT Incidence, Onset, Degree & Reversibility Other Nephrotoxins Hypotension Vasopressor Intensity of Exposure Wong Beringer, IJAA 2011 Page 2 of 8

3 Vancomycin Exposure NT Relationship A Retrospective analysis of 166 adults receiving vancomycin for > 48h, had vanco trough within 96 of therapy initiation and baseline Scr < 2.0. Excluded patients with cystic fibrosis, receipt of contrast dye or vasopressor support. Initial Trough vs AUC 0 24ss Exposure NT (n=21)* Without NT (n=145) P Mean Tr mg/l, sd 14.6, , Tr > 9.9 mg/l 16 (76%) 56 (39%).001 Mean AUC 0 24ss, sd 1318, , AUC 0 24ss > 1300 mg/h.l 7 (33%) 20 (14%).05 Concomitant Nephrotoxins Risk for NT Nephrotoxins Directly organotoxic (AG, amphotericin, iv contrast) Reduced kidney perfusion (furosemide, NSAIDs) Receipt of concomitant NTxns a significant predictor for NT in multivariate analysis. Most studies reported any exposure as risk without specifying the number of nephrotoxins and duration of exposure during vanco therapy. *12.7% experienced NT Lodise, Clin Infect Dis 2009 Wong Beringer, IJAA 2011 Pritchard, A J Med 2010 NT a function of Exposure Intensity Risk of NT without Concomitant NTxns Hidayat 2006; Jeffres 2007; Nguyen 2007; Prabaker 2009; Lodise 2009; McKamy 2011; Cano 2012 Primary Analysis of Non critically ill patients; HD vs SD: Rx duration 9 vs 7 d; ICU Stay 5% vs 3%; Age 62y vs 58y (Mora, ICAAC 2009) Subgroup Analysis (Nguyen, ICAAC 2007) and (Hidayat, Arch Intern Med 2006) Prolonged Duration Risk for NT Multivariate Analysis of Risk Factors for NT Age APACHE II ICU Residence Hypotensive episodes Duration of therapy Concomitant nephrotoxins Requirement for vasopressor therapy Requirement for vasopressor therapy or hypotensive episodes risk for NT by 7 fold (Jeffres 2007, Prabaker 2009) Risk increases incrementally as duration in HD group (Hidayat, 2006): 6% for 7 d; 21% for 8 14 d; 30% for > 14 d Rate of NT from 12 to 22% beyond 10 days Rx (Prabaker, 2009) NT risk by 2 fold after > 2 weeks of Rx (Jeffres, 2007) ICU stay + Furosemide risk for NT by 9 fold (McKamy 2011) Page 3 of 8

4 ICU Residence Risk for NT Applying AKIN Criteria to Detect HD Vanco NT Prospective observational cohort, n=227 elderly received vanco 5 d, excluded CKD or Scr 2 mg/dl 1. AKIN to identify vanco assoc AKI Abrupt (w/in 48 h) in Scr of 0.3mg/dl or 50% or in U.O. UO (< 05ml/kg/h 0.5 for > 6 h) 2. Incidence and degree of injury at the time of AKI diagnosis per AKIN criteria and and the impact of AKI on the process of care (nephrology consults, dosage adjustments for other medications) Lodise, Clin Infect Dis 2009 Minejima, Antimicrob Agents Chemother 2011 Onset and Degree of NT Onset: 4 8 days from start of therapy High Trough, wt > 101 kg, Baseline Clcr, ICU stay impacted time to NT Degree of NT change from baseline Peak Scr : mg/dl Clcr by 35 45% Vanco AKI by AKIN Criteria and Impact of AKI on Outcomes Variable Non AKI (n = 184) AKI (n = 43) Incidence of AKI 19% (43/227) Onset of AKI (mean ± sd) 6 ± 26d day mortality 9 (5%)* 7 (16%)* LOS after VAN initiation (median, IQR) 9 (7, 14)* 13 (10, 23)* Wong Beringer, Int J Antimicrob Agents 2011 Minejima, AAC 2011 Resolution of NT Few studies addressed reversibility of NT 71 81% of patients with Scr values returned to baseline by time of discharge One study reported a 7 day median duration of Scr remaining at 50% above baseline in 21 of 166 patients who experienced NT. Jeffres, 2007; Lodise, 2009; Prabaker 2009; McKamy 2011; Pritchard 2010 AKI Patients by AKIN vs NT Definitions Variable AKIN (n = 26) NT (n = 17) Onset of AKI (mean ±sd) 5.9 ± ±2.4 AKIN: Stage 1 Stage 2 Stage 3 RIFLE: Risk Injury Failure 24 (92%)* 2 (8%)* 0 17 (68%)* 7 (28%)* 1 (4%) 5 (29%)* 10 (59%)* 2 (12%) 3 (18%)* 11 (65%)* 3 (18%) Fold in Scr from baseline 1.6 (1.4, 1.9)* 2.4 (2, 3)* Renal Consultation 3 (12%) 6 (35%) Dosage adjustments of other meds 4 (15%) 7 (41%) LOS after AKI, days (median IQR) 7.5 (3, 13) 11 (5, 20) 28 day Mortality 3 (12%) 5 (29%) Incidence of AKI higher using AKIN (19%, 43/227) vs NT (7%, 17/227) definitions. * p<.05 Minejima, AAC 2011 Page 4 of 8

5 Summary: Safety of HD Vancomycin Therapy 1. NT associated with high trough is a function of intensity and duration of exposure, compounded by concomitant NTxns, vasopressors and physiological impairment. 2. High trough appears to be safe in the absence of factors for NT for limited duration (< 14 d), and dosed using IBW for obese patients. 3. High Dose empirical therapy does not pose signific risk, with NT onset of 4 8 days. 4. Vigilant monitoring to ensure trough levels < 20 ug/ml and for early signs of renal injury (i.e. abrupt change of 0.3 mg/dl in Scr or UOP within 48 h). Telavancin Clinical Trials Phase III RCTs (TLV vs VAN): cssti and pneumonia Overall non inferior efficacy MRSA infections: trend towards higher cure rates Renal impaired patients lower response rates Mortality same in pooled data but higher with TLV in one study of pneumonia No published clinical i l efficacy dt data in CABSI, IE, bone & joint infections or meningitis Renal events (Scr 1.5mg/dL, 50% or 0.5 over baseline) Generally reversible 10% TLV vs 5% VAN (overall, n=3312) 3.4% TLV vs 1.2% VAN (cssti) 2.8 fold higher risk for BMI 35 kg/m 2 (6.4% vs 2.3%) Saravolatz, Clin Infect Dis 2009 Polyzos, PLoS One 2012; Slover, ICAAC 2011 #L Telavancin A lipoglycopeptide structurally related to vancomycin Dual action: inhibits cell wall synthesis + disrupt membrane integrity FDA approved for cssti (Europe for pneumonia) Active vs hvisa, VISA, and MRSA strains with reduced susceptibility to daptomycin or linezolid NOT active vs VRE Saravolatz, Clin Infect Dis 2009 Polyzos, PLoS One 2012 Telavancin Clinical Practice Retrospective cohort, n=21 TLV indications: osteomyelitis (n=5), septic arthritis (n=4), endocarditis (n=4), pneumonia (n=3), sepsis (n=2), cellulitis (n=2), CABSI (n=1), cholecystitis (n=1) Caused by VISA (n=11), MRSA (n=6), DNSSA (n=1) 33% (7/21) developed AKI 50% Scr from baseline to 1.5 mg/dl Marcos, J Antimicrob Chemother 2012 Telavancin Renal Clearance & Dosing Renal excretion: 65% 72% unchanged Primary metabolite excreted in urine, 3 6% of dose Dosage adjustment based on CrCl 10mg/kg q24h, >50 ml/min 7.5mg/kg 5mg/kgq24h, 30 ml/min 10mg/kg q48h, <30 ml/min Hemodialysis: 4h session removes 6% drug AUC and T1/2 is doubled in adults requiring HD CVVH: clearance > normal renal function at UF rate Saravolatz, Clin Infect Dis 2009 Telavancin AKI patient characteristics Variable AKI (n=7) No AKI (14) P Age (mean ± std) 59.2 ± ± BMI (mean ± std) 31.3 ± ± Days of TLV, median (range) 19 (5 52) 16 (3 53) 0.75 Diabetes 57% 29% 0.34 CKD 14% 21% 1.00 History of MRSA Infection 57% 50% 1.00 History of AKI within 6 months 29% 36% 1.00 History of dialysis in last 6 months 14% 0% 0.33 Vanco trough >20mg/L 71% 14% IV contrast 71% 14% *Hypotension (MAP<90 mmhg) and Use of ACEI/ARBs, NSAIDS, vasopressors NOT different Marcos, J Antimicrob Chemother 2012 Page 5 of 8

6 Pt. No. Telavancin AKI outcomes, n=7 Potential Nephrotoxin Baseline Scr Time to AKI on Rx, Scr Time from start to last Scr HD Died 1 IV contrast, ACEI, ; 9 d resolved, 90 d No No vanc, diuretics 2 IV contrast ; 29 d Stage III CKD f/u No No at 7 months 3 NSAID ; 12 d resolved,42 d No No 4 Diuretics, vanc ; 8 d resolved;42 d No No 5* IV contrast, vanc ; 5 d 5.4; 10 d Yes Yes 6 IV contrast, vanc ; 13 d Scr 2.4; 19 d No Yes 7 IV contrast, vanc ; 9 d 6.5; 16 d Yes No Median time to develop AKI = 9 days; Mean GFR of 56 ml/min/1.73m 2 PtNo. 5 had CKD (stage IV), cardiogenic shock, high vanc trough prior to TLV PtsNo. 5 and 7 required permanent dialysis Marcos, J Antimicrob Chemother 2012 Colistin Last resort against MDR gram negatives (Pseudomonas, Acinetobacter, K pneum) Colistin methanesulfonate (colistimethate sodium, CMS) iv formulation inactive prodrug converted in vivo to formed colistin. CMS: ~ 60% renally secreted, with possible conversion of CMS to colistin within tubular cells Colistin: <1% excreted in urine; tubular reabsorption possibly involving organic cation and peptide transporters Biswas, Expert Rev Anti Infect Ther 2012 Li, Lancet ID 2006; Ma, AAC 2009 Telavancin Summary Approved for cssti but..use in practice reserved for patients with infections caused by hvisa, VISA, Dapto nonsusceptible MRSA strains, typically after failed high dose vanco therapy and/or developed AKI on vanco Risks for telavancin associated AKI: Higher risk with BMI 35k kg/m 2 > dosing based on TBW needs to be re evaluated in obese patients due to higher systemic exposure Consider other alternative agents (e.g. linezolid or ceftaroline) in patients who had been treated with high dose vanco and have pre existing risks for AKI (prolonged therapy at high trough, other nephrotoxins, hypotension, prior AKI) Developed AKI due to high dose vancomycin therapy; also, lower efficacy observed for patients with renal insufficiency receiving telavancin in clinical trials for cssti or pneumonia Colistin Dosing Inconsistent recommendations depending on commercial products used Colomycin (Europe): 4 6 mg/kg/d CMS, max 480mg/d Coly mycin (US): mg/kg/d CMS, max 800mg/d Current regimens suboptimal for ICU patients Delayed attainment of steady state conc.? Need for Loading Dose PK/PD index fauc/mic best predictor of efficacy, very modest post antibiotic effect. Bergen PJ, Curr Opin Pharmacol 2011 Li, Lancet ID 2006 Non Nephrotoxic Alternatives for MRSA Infections Linezolid Bone marrow suppressive effects; Higher mortality in linezolid treatment arm in an open label randomized trial of patients with catheter related bacteremia or catheter site infections who had Gm neg alone, mixed Gm+/Gm or no infection at study entry (Gm+ mortality same as comparators vanc/oxac) Daptomycin Potential cross resistance with vancomycin Quinupristin/dalfopristin Potent CYP3A4 inhibition; LFTs elevation; arthralgias Ceftaroline limited clinical data for MRSA pneumonia or bacteremia Colistin associated AKI NT rate ranges 10 37% of patients on CMS with doses 5 12mg/kg/day using a variety of definitions for NT U.S. studies using RIFLE criteria i NT 31 45% Risk (1.5x Scr, >25% GFR): 8 13% Injury (2x Scr, >50% GFR): 10 17% Failure (3x Scr, >75% GFR): 4 17% Onset within 5 7 days; most were reversible w/in 2 wks DC Biswas, Expert Rev Anti Infect Ther 2012; Falagas, Int J Antimicrob Agents 2010 Hartzell, Clin Infect Dis 2009; DeRyke, AAC 2010; Doshi, Pharmacother 2011; Pogue, Clin Infect Dis 2011 Page 6 of 8

7 Risk Factors for Colistin associated AKI Dose dependent NT Pogue, Clin Infect Dis 2011 N=126, 43% NT Multivariate regression Multiple nephrotoxins risk > 6 fold Obesity BMI 31.5 kg/m2 Dosing on TBW in obese patients rather than on IBW risk by 13.2 fold Duration > 14 days risk by 3.7 fold Hartzell, Clin Infect Dis 2009; DeRyke, AAC 2010; Doshi, Pharmacother 2011; Pogue, Clin Infect Dis 2011; Gauthier, AAC 2012 Non nephrotoxic alternatives for MDR Gram negative infections to Colistin Carbapenem resistant K. pneum Fosfomycin Marketed in US as oral only for UTI Tigecycline: Not for bacteremia, urinary tract, pneumonia MDR Acinetobacter Tigecycline; minocycline Combinations: Amp/sulb + rifampin/cefepime/imip/mero MDR Pseudomonas Combinations for synergy Maximize PD of individual agent (Continuous or Prolonged infusion of B lactams) Kanj, Mayo Clin Proc 2011 Neonakis, IJAA 2010 Mechanism of Colistin NT Exact mechanism unknown Increase membrane permeability, cell swelling and lysis Oid Oxidative i stress Current Assessment of Renal Function BUN, Scr Insensitive, non specific, and delayed Changes measurable only after 30 50% of final tissue damage has occurred (Duarte, 1993) Influenced by non renal factors: race, age, gender, total body volume, drugs, muscle metabolism, tbli and protein ti intake Incorporate standardized definition of AKI to monitor patients in practice Need for more specific and early biomarkers of AKI to allow early detection for prompt intervention Duarte, Clin Lab Med 1993 Protection from Colistin induced AKI AKIN Criteria for Diagnosis of AKI Avoid concomitant nephrotoxins Animal studies with anti oxidants: Ascorbic acid N acetylcysteine Melatonin Yousef, J Antimicrob Chemother 2012 Ozyilmaz, Intensive care Med 2011 Yousef, Antimicrob Agents Chemother 2011 Ricci, Nat Rev Nephrol 2011 Page 7 of 8

8 Spectrum of AKI Vaidya, Annu Rev Pharmacol Tox 2008 Clinical Qualification of Urinary Biomarkers for Diagnosis of AKI A panel of biomarkers will be necessary for clinical utility Disparate settings under which kidney injury occurs Different biomarkers provide different information on the location and extent of tubular injury & functional consequences of tubular injury Consortium clinical trials initiated to validate a panel of biomarkers for drug induced d daki aminoglycosides, cisplatin (U.S.) IV contrast (Europe) Endpoints: 1. Compare biomarker specificity and sensitivity to Scr in detecting nephrotoxic drug exposure 2. Validate threshold values for biomarkers in diagnosing AKI. Ferguson, Toxicol 2008 Goodsaid, CPT 2009 Urinary Biomarkers in Early Diagnosis of AKI Upon injury, enzymes present in the tubular epithelial cell may be released into the urine secondary to leakage from damage or secondary to intensified enzyme induction during the repair and regeneration process. Dose dependent correlated to degree of tissue damage present Enzyme detection may provide clues to the site and severity of tubular injury based on cellular origin of enzymes: Proximal vs tubule brush border, lysosome, or cytoplasm * Early markers of injury NOT necessary of kidney function * Specificity for AKI varies dependent on physiologic conditions * Urinary biomarkers may be unstable requiring fast and special processing Han, Kidney International 2008 Ferguson, Toxicol 2008 Goodsaid, CPT 2009 Summary Emergence of multidrug resistant pathogens necessitates use of nephrotoxic antibiotics NT a function of dose and duration Avoidable risks: concomitant nephrotoxins More studies needed to determine best weight to base dosing in obese patients Use of standardized diagnostic criteria of AKI will aid in earlier detection of AKI and for comparison of nephrotoxicity rates across studies and populations. Future monitoring can be optimized with use of a panel of urinary biomarkers that are more sensitive and specific than serum creatinine. Promising Candidate Biomarkers of AKI Biomarker Origin Indicator Value NAG (N Acetyl βglucosaminidase KIM 1 Kidney injury molecule 1 NGAL (neutrophil gelatinase assoc lipocalin) Proximal tubule lysosomal enzyme; false elevation in rheumatoid arthritis, impaired glucose tolerance, hyperthyroidism Type I cell membrane glycoprotein; expression upregulated in proximal tubular epithelial de differentiated cells during regeneration and repair Synthesized during granulocyte maturation in the bone marrow; Upregulated in proximal tubule cells after ischemic injury Highly sensitive indicator of AKI; urinary NAG 12h to 4 d before Scr Highly sensitive & specific for AKI ; vancomycin, contrast dye, y,gentamicin Early indicator of AKI after cisplatin admin; urinary NGAL 1 3 days before Scr QUESTIONS? Cys C (Cystatin C) Low M.W. protein extracellular inhibitor of cysteine proteases; filtered by glomerulus and reabsorbed but not secreted by proximal tubule cells Sensitive serum marker of GFR; Urine Cyc C in tubular dysfunction Ferguson, Toxicol 2008 Page 8 of 8