Cystatin C: A New Approach to Improve Medication Dosing

Cystatin C: A New Approach to Improve Medication Dosing Erin Frazee Barreto, PharmD, MSc, FCCM Assistant Professor of Pharmacy and Medicine Kern Scholar, Center for the Science of Health Care Delivery Mayo Clinic, Rochester, Minnesota

Disclosures Consultant, Fast Biomedical

Objective Discuss how novel renal biomarkers can be leveraged to guide drug dosing in critically ill patients

Case: A.B. 74yo M adm. for septic shock due to a UTI PMH: Alcoholic cirrhosis, stroke with hemiparesis and urethrocutaneous fistula with recurrent UTIs Fluids, vasopressors, cultures were drawn Starting cefepime, gentamicin, vancomycin Renal parameters in the first six hours Serum creatinine (SCr) 0.7 mg/dl Urine output (UOP) 25 cc/h (0.25 ml/kg/hr)

Thoughts About His Dosing General thoughts How hard is this disease to treat? How sick is the patient? How wide are the therapeutic ranges? Renal assessment SCr 0.7 mg/dl is normal, UOP 0.25 ml/kg/hr is low which sends mixed messages about renal function Maybe low SCr is due to his age, deconditioning, and cirrhosis and shouldn t be trusted? Maybe he has acute kidney injury but SCr is lagging? Net: Uncertainty, inaccuracy, imprecision

Biomarkers for Drug Dosing Attributes Ideal SCr Endogenous Easily, rapidly, inexpensively measured Detects even small GFR changes Quick response to changing GFR Few confounders GFR: Glomerular filtration rate; SCr: Serum creatinine

Mayo Clinic Renal Dosing Antibiotic Handbook Vancomycin Dosing Electronic Record Prompts and Calculations

Cystatin C (CysC) Low molecular weight protein Produced by all nucleated cells Renally-eliminated via glomerular filtration, reabsorbed and catabolized in the proximal convoluted tubule Easily measured in the serum and urine Mussap M, et al. Crit Rev Clin Lab Sci 2004;41(5-6):467-550. Levey AS, et al. Clin Pharmacol Ther 2017;102(3):405-19.

egfr Biomarker Properties Attributes Ideal SCr CysC Endogenous Easily, rapidly, inexpensively measured Detects even small GFR changes Quick response to changing GFR Few confounders GFR: Glomerular filtration rate; SCr: Serum creatinine; CysC: Cystatin C

CKD EPI egfr vs mgfr SCr egfr vs mgfr CysC egfr vs mgfr SCr and CysC egfr vs mgfr Meeusen JW; Cin Chem 2015;61:10:1265-72.

Simulated Change to CKD-EPI Weighted Kappa (95% CI) compared to egfr CG Frequency of doses relatively lower with egfr CG Frequency of doses similar to egfr CG Frequency of doses relatively higher with egfr CG egfr Cr 0.73 (0.68,0.79) 34 (11%) 237 (77%) 37 (12%) egfr cysc 0.42 (0.35, 0.5) 38 (12%) 152 (49%) 118 (38%) egfr Cr-cysC 0.65(0.6, 0.71) 26 (8%) 209 (68%) 73 (24%) egfr: Estimated glomerular filtration rate from Cockcroft Gault creatinine clearance (egfr CG ), or CKD EPI with creatinine (egfr Cr ), cystatin C (egfr CysC ), or the combination of creatinine and cystatin C (egfr Cr-CysC ) Take Home: Pharmacokinetic analyses and drug-specific dosing models should be developed and tested Peters BJ, et al. Unpublished, under review.

Medication Use and CysC Systematic review through 09/2017 34 studies, 16 different drugs, 3455 patients Cockcroft-Gault was the most commonly reported standard of comparison for egfr egfr CysC equations varied Findings CysC level and egfr CysC better predicted drug levels and drug clearance than SCr and egfr Cr Rarely was the combined use of both biomarkers evaluated Only infrequently were target attainment and clinical outcomes studied Barreto EF, et al. Unpublished, under review.

Vancomycin Dosing Hypothesis: Development and use of a CysCguided model for vancomycin dosing in the ICU would improve accuracy and precision of dosing and overall target attainment Part 1 Derivation Part 2 Implementation Part 3 Testing N = 173 hospitalized adults March to October 2012 3 ICUs at Mayo Clinic Rochester December 2013 N = 399 critically ill adults December 2013 to May 2015

Vancomycin Dosing Dose 4 Dose 3 Vancomycin level (mg/l) Goal trough range Vancomycin Dose 1 Dose 2 Time Baseline (SCr and cystatin C collection and model construction) Steady-state vancomycin trough Frazee EN, et al. Crit Care 2014;18(3):R110.

Multivariate Models egfr CG Model R 2 Predicted Trough Achievement 0.269 33 (26-40%) Pre-trough total dose Dosing interval egfr CG (ml/min) egfr Cr-CysC Model R 2 Predicted Trough Achievement 0.580 54 (45-61%) Pre-trough total dose Dosing interval CKD-EPI egfr Cr-CysC (ml/min) Frazee EN, et al. Crit Care 2014;18(3):R110.

New Nomogram Weight (kg) 70-79 80-89 90-99 Goal 10-15 mg/l Goal 15-20 mg/l egfr (CKD-EPI cr-cys ml/min) 60-69 70-79 80-89 90-99 100-109 1500 q24 800 q12 1000 q12 1200 q12 800 q8 1200 q12 1350 q12 1000 q8 1200 q8 1400 q8 1500 q24 800 q12 1000 q12 1200 q12 800 q8 1200 q12 1350 q12 1000 q8 1200 q8 1400 q8 1500 q24 1700 q24 1000 q12 1200 q12 1350 q12 1200 q12 1350 q12 1000 q8 1200 q8 1400 q8 Frazee EN, et al. Am J Kidney Dis 2017;69(5):658-66.

New Nomogram: Candidacy Inclusion 18 years Hospitalized in one of three ICUs under evaluation Prescribed intravenous vancomycin Consistent regimen planned with an 8, 12, or 24 hour dosing interval Exclusion > 1 dose of vancomycin before ICU admission GFR < 20 ml/min Dialysis-dependent Inappropriate candidate for scheduled dosing (i.e. acute kidney injury) Weight < 40 kg BMI > 40 kg/m 2 Frazee EN, et al. Am J Kidney Dis 2017;69(5):658-66.

Implementation Logistics Patient eligibility and need for first vancomycin dose assessed CysC added to stored serum or drawn Pharmacist-directed dosing and communication Steady state level checked De-escalation and adjustments per usual practice Frazee EN, et al. Am J Kidney Dis 2017;69(5):658-66.

Comparative Study Cohort study New nomogram vs historical control with egfr CG dosing Primary endpoint Initial steady state therapeutic vancomycin trough Secondary endpoints Clinical failure in confirmed gram-positive infections ICU, hospital length of stay, 28-day mortality Nephrotoxicity

Trough Distribution Frazee EN, et al. Am J Kidney Dis 2017;69(5):658-66.

Target Achievement 60% 50% Subtherapeutic Therapeutic Supratherapeutic 52% 50% Percent of Patients 40% 30% 20% 28% 20% 36% 14% 10% 0% Control Group Intervention Frazee EN, et al. Am J Kidney Dis 2017;69(5):658-66.

Secondary Endpoints Characteristic Control Intervention (N = 264) a (N = 135) a P Value Composite of nephrotoxicty or death within 7 days of vancomycin (N; %) 38 (14) 17 (13) 0.62 Treatment failure at day 7 (N; %) b In MRSA patients (N; %) 37 (34) 8 (30) 12 (29) 3 (33) 0.50 1.00 Intensive care unit length of stay (days) 2.5 (1.3, 6.5) 2.9 (1.5, 6.4) 0.78 Hospital length of stay (days) 10.9 (5.6, 20.2) 10.3 (6.2, 32.0) 0.16 28-day all-cause mortality (N; %) 35 (13) 24 (18) 0.23 AKI: acute kidney injury; RRT: renal replacement therapy a : Values expressed as median (IQR) unless noted b : N (%) of the 150 individuals (Control: N = 108; Intervention: N = 42) with microbiologically confirmed gram-positive infections Frazee EN, et al. Am J Kidney Dis 2017;69(5):658-66.

Case: A.B. Factors A.B. Demographics 74yo M, 99 kg, BMI 31.6 kg/m 2 SCr egfr CG 0.7 mg/dl (normal 0.6-1.1 mg/dl) 130 ml/min Cefepime 2g IV q8-12h Observed level:?? (Many medications go unmonitored) Vancomycin 15-20 mg/kg q8h (1500-2000mg q8h) Observed level: 29.7 (goal 15-20mg/L; risk for toxicity)

Case: A.B. Factors Serum creatinine Cystatin C egfr CG CKD EPI egfr Cr-CysC A.B. 0.7 mg/dl (normal 0.6-1.1 mg/dl) 2.0 mg/l (normal 0.6-1.1 mg/l) 130 ml/min 64 ml/min Cefepime 1-2g IV q12h Vancomycin 1500mg q24h Observed level: 14.7 (goal 10-15mg/L; therapeutic)

Summary and Pearls Existing biomarkers have limitations Drug specific dosing models are needed rather than universal use of new formulas Operationalizing anything other than SCrbased dosing is a multidisciplinary effort Automation where possible (lab draw, calculations, resultant dose) NKF egfr calculator (expressed in ml/min) QxMD calculator/app No egfr formula or dosing tool should replace clinical judgement Barreto EF, et al. Pharmacotherapy 2018 (In press).