2017/3/7. Evaluation of GFR. Chronic Kidney Disease (CKD) Serum creatinine(scr) Learning Objectives

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1 Evaluation of egfr and mgfr in CKD Use of CKD staging with case scenario Assessment of kidney function in CKD in adults Learning Objectives 台大雲林分院楊淑珍藥師 2017/03/11 Chronic Kidney Disease (CKD) Based on 3 or more months of either kidney damage or egfr <60ml/min/1.73m 2 Adds refinements based on cause, egfr and albuminuria categories Stage GFR Description G1 90 Normal or high G Mildly decreased G3a Mild-moderate decrease G3b Moderate decrease G Severely decreased G5 <15 Kidney failure or ESRD Evaluation of GFR Ideal filtration makers Freely filtered by glomeruli Not reabsorbed Not secreted Not metabolized Calculated by measuring the clearance of inulin,iothalamate or iohexol (mgfr) GFR=Uinulin V/Pinulin Complex,expensive and difficult the rate excreted in the urine= plasma removal rate Serum creatinine(scr) Not a ideal maker of GFR than inulin 15% secretion in proximal tubule reabsoption may occur at very low urine flow exceeds inulin clearance by 10-20% in normal and, >50-60% in advanced kidney disease Variability in measurement Variable amount and turnover 2012 KDIGO suggest use a GFR rather than SCr Increase serum creatinine Kindey disease Eating meat Exercise Ketoacidosis Drugs (trimethoprim,cimetidine,flucytosine,some cephalosprines,steroids) Decrease serum creatinine Reduced muscle mass (amputation,muscle wasting/paralysis) Malnutrition Ageing Liver disease 1

2 Unstandardization of Creatinine Assay Measured ClCr(1) Adult reference range( Not calibrated serum creatinine) ml/min for enzymatic method and ml/min for Jaffe-based test Lowest errors with GFR< 60 ml/min/1.73m 2 (-17% ~ +3%) Highest errors with GFR 60 ml/min/1.73m 2 (-31% ~ +11%) Calibrated assay from 2009 Standardized to the reference method IDMS (isotope dilution mass spectrometry ) Classical creatinine clearance determination Diurnal variation Timed 24hr urine collection Collection errors or incomplete or volume measurement Shorter intervals Confounded by bladder emptying incompletely Exceeds GFR Clcr= Urine creatine(mg/dl) Urine volume(ml/24hr) Plasma creatinine(mg/dl) 1440 Measured ClCr(2) Timing Instead of egfr Extremes of age Severe malnutrition /Vegetarian diet/skeletal muscle disease Obesity Rapidly changing renal function Need for accurate clearance measure the same serum creatintin but very different egfr! All creatinine- based equations should be used with caution with abnormally high or low levels of muscle mass Ovadia Shemesh et al.limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney International Measured GFR(mGFR) Creatinine base egfr and eclcr Very accurate Exogenous makers Disadvantages egfr Modification of Diet in Renal Disease Study inulin(gold standard) expensive 51 not commercially Cr-EDTA probable tubular reabsorption CKD-EpidemIology collabration eclcr Cockroft-Gault iohexol (Omnipaque) # expensive probable tubular reabsorption iothalamate probable tubular reabsorption # Not radioactive Marijn Speeckaert et al.assessment of renal function. Oxford textbook of Clinical Nephrology 4 th edition. 2

3 Equation Study population Remark Equation Variables Formulation Cockroft-Gault Age,weight,s ex,scr Cockroft-Gault men,18-92 yrs Clcr from ml/min(SCr mg/dl) No liver or renal disease Not adjust for BSA Creatinine clearance factor 0.85 is hypothetical for female Not be re-expressed for IDMStraceable creatinine values * * multiply by if black Age,sex, race,scr 186 (SCr) (Age) (0.742 if female) 175 (SCr) (Age) (0.742 if female) 141 MIN(SCr/K,1) a MAX(SCr/K,1) (0.993) age 1.018(if female) 1.159(if Black) * patients with nondiabetic CKD 60% men,ages yrs Mean SCr of 2.3mg/dl and mean GFR as 40ml/min/m 2 88% white 8254 individuals from 10 studies and validated in additional 16 studies containing 3896 individuals measure GFR ml/min/m 2 (mean 68 ) mean age 47,mainly<65yr Adjust for BSA IDMS traceable P30 of mgfr: 91% Improve egfr particularly among >60 ml/min/1.73m 2 Reduce the rate of false-positive diagnose of CKD stage 3 in patient without CKD with lower bias Cockroft- Gault Preferred Normal Scr About 70 kg Mostly Men egfr< 60ml/min/1.73m 2 Not validate CKD stage 2-4 Overestimation of GFR by up to 20% in individuals with stages 2-4 CKD More variability than (P30 of mgfr:50~70 % vs 83%) Children,pregnant women and elderly Ethnic subgroups other than Caucasians and African Americans Diabetes Normal kidney function Few participants older than 70(>65yr:13%,>70yr :3%) Underestimate of true GFR by 29% in followings: Healthy Kidey donors Type 1 DM with normal SCr Discrepancies of among healthy compared with CKD Increasing serum creatinine in CKD Most likely due to a reduction in GFR Recommended reporting of egfr of in health More likely due to non-renal causes (increased muscle mass or protein intake) not calibrated SCr A. egfr of should be reported as greater than for less precise in CKD stage1-2 Use the equation when egfr >60ml/min/1.73m 2 Risk of false-positive diagnoses of CKD stage 3 Wrong decision making as followings: Reduction in dosage of drug excreted by the kidney Avoid contrast media for imagine procedures Avoidance of phosphate-based enemas in preparation for colonscopy Lower targets for CV risk factors Year 53 CKD history NO Scr(mg/dl) 1.0?? What is the egfr when you know SCr assay not calibrated? Importantly,may lead to insufficient drug dosing! What is the CKD stage? Year 60 CKD history Yes Scr(mg/dl) 1.9?? 3

4 Use C-G equation in case with normal Scr and without history of CKD Use in case with abnormal Scr and history of CKD Language reports as Greater than or equal to with uncalibrated SCr assay Take BSA into account Accuracy of Weight Adjustment in C-G Cockroft- Gault Nonnormalised (ml/min) Comments For CKD detection using BSAadjust C-G formula Classification BMI Weight in C-G Normalised (ml/min/1.73m 2) when adjust dose,conversion to actual GFR or Non-normalised GFR Under-weight <18.5 Actual BW Normal weight 18.5~24.99 IBW Over-weight 25~29.99 ABW Kidney function is proportional to kidney size Obese 30 ABW Mary A. Winter.Impact of Various Body Weights and Serum Creatinine Concentrations on the Bias and Accuracy of the Cockcroft-Gault Equation.Pharmacotherapy Cockcroft-Gault Equation(C-G) Dosing Recommendation(1) Overweight or obese Under-estimate using ideal body weight(ibw) Over-estimate using actual body weight (ABW) Resolution: 1. Adjust body weight when BMI over 25kg/m 2 2. Calculate a range using IBW and ABW Adjust body weight=ibw+0.4 (ABW-IBW) Equation Role in drugs Concordance Cockroft-Gault Widely used in PK studies 1998 FDA administration-approved prescribing information No evidence of body weight modification are more accurate predictors of GFR * Use of IDMS-traceable creatinine values will result in a more accurate egfr for less variation Not available at the time of FDA guidance to industry FDA update guidance in 2010 Little difference in the drug dose using either equation Agreement between egfr and eclcr was 88~89% Expression as ml/min in very large or small in size 4

5 Rationales of assessment of kidney function for drug dosing purpose Dosing Recommendation(2) Utilize egfr or ecrcl for drug dosing If using egfr in very large or small patients,adjustment for BSA Consider using measured CrCl or mgfr in whom egfr and ecrcl provide different estimation or individuals are likely to be inaccurate (ex.extremes of body size or muscle mass..) FDA update the guidance in 2010 Provide drug dosing recommendations on the basis of both an eclcr and egfr May changes to egfr based dosing recommendations for newly developed drugs When egfr based differed with eclcr for drug dosing Risk versus benefit for medication Narrow or wide therapeutic index Follow up clinical status and do TDM when available CKD and Drug Dosing: Information for Providers No estimating equation is perfect and can replace clinical judgment! Year 60 Body weight(kg) 65 BMI (kg/m 2 ) BSA(m 2 ) # 1.79 Assess the dosing of ciproxin intravenously for HCAP? Year 90 Body weight(kg) 65 BMI (kg/m 2 ) BSA(m 2 ) # 1.79 Year 40 Body weight(kg) 60 BMI (kg/m 2 ) 19 BSA(m 2 ) # 1.72 What is the egfr or eclcr to express values uniformly in ml/min?? Year 40 Body weight(kg) 120 BMI (kg/m 2 ) 38 BSA(m 2 ) #