Estimating GFR: From Physiology to Public Health. Outline of Presentation. Applications of GFR Estimations

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1 stimating FR: From Physiology to Public Health Tufts: Andy Levey, Lesley (Stevens) Inker, Chris Schmid, Lucy Zhang, Hocine Tighiouart, Aghogho Okparavero, Cassandra Becker, Li Fan Hopkins: Josef Coresh, Jane Manzi, Morgan rams Utah/Cleveland Clinic: Tom reene, Liang Li, Fred Van Lente UMN: John ckfeldt, Cathie Leiendecker Foster Penn: Harv Feldman, Marshall Joffe, Dick Landis NIDDK: Paul ggers, John Kusek No conflicts to declare rant Support: NIH UO1 DK NIH UO1 DK NIH UO1 DK National Kidney Foundation Outline of Presentation Current applications FR measurement Principles of FR estimating equations Performance of CKD-PI creatinine and cystatin C equations Associations of efr with outcomes New KDIO guidelines Summary and conclusions FR is one of many kidney functions xcretory (filtration, reabsorption, secretion) ndocrine (renin, erythropoeitin, vitamin D) Metabolic (degradation of low molecular weight proteins and drugs) Serum creatinine as a filtration marker Measured 280 millions times per year in US stimated FR reported more than 80% of clinical laboratories Substantial impact on clinical practice, research and public health Current methods of study of renal function may be too elaborate for general clinical application, but no method is to be disdained if it can aid significantly in deciding the issue between life and death. Smith HW. The Kidney: Structure and Function in Health and Disease. Oxford University Press, NY 1951 Applications of FR stimations Routine estimation for clinical care Interpreting the symptoms, signs, and laboratory abnormalities that may indicate kidney disease drug dosing detecting and managing chronic kidney disease and assessing the prognosis FR <60 ml/min/1.73 m2 for >3 months diagnostic criterion for CKD associated with an risk of adverse outcomes, including death Classification of CKD Prognosis Cause of CKD (C) by FR and Albuminuria FR () Albuminuria Categories: (A) KDIO 2012 FR Categories, Description and Range (ml/min/ 1.73 m 2 ) 1 2 3a 3b 4 5 normal or high mildly mildly to to kidney failure > <15 Albuminuria Categories, Description and Range A1 A2 A3 normal to mildly <30 mg/g <3 mg/mmol mg/g 3-29 mg/mmol >300 mg/g >30 mg/mmol Percentage Risk Categories of US Population Moderate by efr 73% and Albuminuria High 18% Category: KDIO 2012 and Very High 9% NHANS Persistent Albuminuria Categories, Description and Range A1 A2 A3 normal to mildly <30 mg/g <3 mg/mmol mg/g 3-29 mg/mmol >300 mg/g >30 mg/mmol normal or 1 > high mildly CKD 2Stage : % Stage 3a, A1: 3.6% FR Categories, 3a Description and Range (ml/min/ 3b 1.73 m 2 ) 4 5 mildly to to kidney failure CKD 11.5% <

2 Premises FR is the measure of kidney function we wish to assess. efr from serum levels of filtration markers is more practical than mfr for routine clinical assessment. We want clinical laboratories to report efr when we measure the filtration marker. We need to recommend a single equation for laboratories for each filtration marker for routine efr reporting. mfr efr outcomes Relationship of Measured and stimated FR to Clinical Outcomes CKD-PI mfr efr outcomes Performance creatinine C MDRD Study CKD-PI cystatin C CKD-PI panel CKD-PC Associations drug dosing disease definition prevalence prognosis True FR FR is a physiological property. It is variable, influenced by body size, time of day, feeding. It cannot be measured directly. It is assessed from clearance measurements or serum levels of filtration markers. Measured and estimated FR are associated with error (bias and imprecision). Filtration marker handling (non-fr determinants) Clearance procedures Assays True FR is a hypothetical concept. Operational definition average value over 1-2 days. Inulin (5200) Stokes instein radius (nm) Haraldsson, Nystroöm, Deen. Physiol Rev 88: , 2008 Filtration Markers Substances that are filtered by the glomeruli which can be used to measure or estimate the FR xogenous or endogenous Ideal properties Freely filtered MW <20,000 d MR <1.5 nm not protein bound Not reabsorbed or secreted by the tubule asy to measure Clearance Method Urinary Continuous IV Urinary Bolus IV or SC Urinary or Plasma Bolus IV Clearance Measures and Filtration Markers Filtration Marker Type Name Comments Inulin old standard xogenous 125 I-Iothalamate Secreted 51 Cr-DTA Not available in the US 99m TC-DTPA Quality Control Iohexol Urinary ndogenous Creatinine Assay Secreted Collection errors

3 Relationship of Plasma Level of ndogenous Filtration Markers to FR (cells) P (gut, liver) FR = FR x P + = FR x P + FR = ( + ) / P Reciprocal relationship between FR and P, modified by non-fr determinants Relationship of Plasma Level of ndogenous Filtration Markers to FR (cells) P (gut, liver) FR = FR x P + = FR x P + FR = ( + ) / P stimating equations use regression to relate measured FR to P using surrogates for non-fr determinants Relationship of Plasma Level of ndogenous Filtration Markers to FR (cells) P (gut, liver) FR = FR x P + = FR x P + FR = ( + ) / P Assay standardization and calibration Development and Validation of stimating quations Separate datasets for development and validation populations Study populations with a wide range of clinical characteristics and FR, representative of the clinical populations in which equations are to be applied. Reference methods for mfr and serum concentrations Surrogates with a priori relationship to non-fr determinants Linear regression of log mfr on log P Standard metrics for evaluation: bias, precision, accuracy, and classification-reclassification. Creatinine Creatinine-Based FR stimating quations (muscle) S FR = FR x S + - = FR x S + FR = ( - - ) / S Cockcroft-ault formula C cr (ml/min) = (140-age) x weight *0.85 if female 72 S cr MDRD Study equation FR (ml/min/1.73 m 2 ) = 175 x (S cr ) x (age) x (0.742 if female) x (1.212 if African American) (gut) Stevens and Levey. JASN : Age, sex, race, weight CKD-PI equation FR = 141 x [min(scr/κ),1) α x max(scr/κ),1) ] x Age x [if female] x [1.157 if AA] α is for females and for males; min indicates minimum of Scr/ or 1, and max indicates maximum of Scr/ or 1

4 Performance of the MDRD Study and Cockcroft-ault (C) equations before and after calibration of serum creatinine assays MDRD Before After % P C Before After % P Performance of the CKD-PI and MDRD Study quations All P All P After Calibration Before Calibrated N=5504 Stevens et al AJKD 2007 N=3896, Levey et al. Ann Intern Med 2009: 150: FR Distribution and Risk Relationships in P Mean FR < % % Reclassification of efr Categories by CKD-PI and Risk Implications in P Cohorts ACM CVM SRD N = 940,366 in 25 cohorts, Matsushita JAMA HR adjusted for age, sex, race, smoking, SBP, total chol, diabetes, history of CVD and BMI. NRI: ACM = 0.11 ( ); CVM = 0.12 ( ); SRD = 0.07 ( ) Net reclassification improvement (NRI) by CKD PI (P) Cystatin C (all cells, factors?) U X V = FR x S - - = FR x S S FR FR = ( + ) / S MDRD CKD PI MDRD CKD PI MDRD CKD PI (?) Age, sex,?

5 Coefficients for Variables in the CKD-PI quations quations Variable Creatinine* Cystatin C# Creatinine and Cystatin C# Creatinine Scr Scr (above the knot) Cystatin C - Scys Scys (above the knot) Age Age Age Age (linear) Female Sex (above the knots) Black Race *quation development in 8254 subjects (Inker, NJM 2012). #quation development in 5352 subjects (Levey, Ann Intern Med 2009). Performance of quations in the Validation Dataset (N=1119) quations Bias Precision (IQR) Accuracy (P 30 ) Creatinine alone (CKD-PI) Cystatin C alone Creatinine-cystatin C * 91.5* Average of creatinine alone and cystatin C alone *P <0.001 compared to creatinine alone or cystatin C alone Inker, NJM 2012 Bias (Median Difference) by Subgroup FR Distribution and Risk Relationships in P Mean FR < % % % N = 90,750 participants in 11 cohorts, Shlipak NJM 2013 Reclassification of efr Categories by efrcr-cys vs. efrcr and Risk Implications in P Cohorts ACM CVM SRD HR adjusted for age, sex, race, smoking, SBP, total chol, diabetes, history of CVD, BMI and albuminuria. NRI: ACM = 0.13 ( ); CVM = 0.10 ( ); SRD = ( ) 2012 KDIO uidelines Related to FR stimation and eneral recommendations and Recommendations regarding efrcreat Confirmation of efrcreat <60 using cystatin C and Recommendations regarding efrcys

6 Next steps New cohorts Novel filtration markers BTP B2M others Panel efr Summary and Conclusions (1) CKD-PI creatinine equation compared to MDRD Study equation More accurate for estimating measured FR Lower CKD prevalence More accurate risk predictions CKD-PI cystatin C equation compared to creatinine equation Not more accurate for estimating measured FR May be more accurate for low BMI May be useful when race cannot be specified More accurate risk predictions CKD-PI combined creatinine and cystatin C equation compared to equations using either marker alone More accurate for estimating measured FR May be useful for confirmation of efr <60 They should be the standards for comparison to new equations. They should be evaluated outside North America and urope. Summary and Conclusions (2) FR estimating equations are here to stay. They are based on principles of physiology and have been developed in large and diverse populations using standardized assays and rigorous statistical methods. They are useful in clinical practice, research and public health. Their appropriate use requires understanding of assays and non-fr determinants of filtration markers and principles of diagnostic testing. They can be improved by development in representative populations and use of new filtration markers. New filtration markers should be expressed as efr. The goal should be routine availability of an estimated FR from a panel of markers as accurate as measured FR. CVD Drug toxicity Conceptual Model for CKD Metabolic/hormonal Other (Infection, cognitive impairment, frailty, etc) Remission Kidney Outcomes Progression Conceptual Model for CKD Conceptual Model for CKD Biopsy urine alb/creat Markers Transplant >30 mg/g efr <60 efr <15 or dialysis 9.7 m 4.8% 7.7 m 13.5 m 6.7% 0.4 m 0.2% >3 mos 23.6 m 11.7% NHANS , Levey et al, Ann Intern Med 2009