Page 1. Disclosures. Main Points of My Talk. Enlightened Views of Serum Creatinine, egfr, Measured GFR, and the Concept of Clearance

Transcription

1 1 Enlightened Views of Serum Creatinine, egfr, Measured GFR, and the Concept of Clearance John Toffaletti, PhD Director of Blood Gas and Clinical Pediatric Laboratories Professor of Pathology Duke University Medical Center Chief of Clinical Chemistry; VA Med Center Durham, NC Disclosures Receive research support from Instrumentation Laboratory. Receive consultation fees from Roche Diagnostics and Instrumentation Laboratory. Main Points of My Talk What is clearance? Creatinine is a better renal function test than often believed. Does the CKD-EPI egfr improve clinical diagnosis? What benefits will IDMS standardization provide? Actual measured GFR may not be the optimal renal function test. A few points on cystatin C. The future of egfr and creatinine measurements. Page 1

2 2 Diagram of Glomerulus r Diagram of a Human Nephron GFR H 2O H 2O H 2O Urine Production What is Clearance? Certainly An Awkward Concept! Originally developed by physiologists to characterize how the kidneys handled various compounds: For compounds that are 1% filtered and neither secreted nor reabsorbed in tubules: Clearance = GFR Logically, clearance should be in units of mmol/min. However, actual units of ml/min create awkward definition that is confusing and does not occur: amount of plasma that flows through renal glomeruli per minute with complete removal of creatinine to account for creatinine excreted into urine Clinically, we use Clearance only to determine the GFR: Creatinine, inulin, iothalamate clearances all similar. Page 2

3 3 Use of Creatinine/Iothalamate/Inulin and Urine Volume to Estimate Glomerular Filtration Rate GFR ml/min 1 1 H 2 O 1 5 H 2 O H 2 O 8 Creatinine/ iothalamate/inulin (Serum) Urine Volume ml/min Creatinine/ iothalamate/inulin (Urine) 1 Equation for Creatinine Clearance (Similar to Iothalamate or Inulin Clearances) Creatinine clearance is really an estimate of the GFR: GFR (ml/min) = urine production (ml/min) x urine creatinine plasma creatinine Measures what s left of the original glomerular filtrate Indicates how much the original glomerular filtrate has been concentrated What Would be the Ideal Marker for Chronic Declining Kidney Function? Measured GFR? Has large individual and population variation. Very cumbersome test. Serum marker : creatinine or cystatin C? Practical, and both have small within-individual variations. Number of lost functioning nephrons? Yes, but we cannot measure this, so we are stuck with GFR or serum marker. This has led to the development of the egfr (estimated GFR) calculated from the plasma creatinine. Page 3

4 4 Plasma Creatinine as a Renal Function Test Good: An increase is usually specific for diminishing renal function. Good: Within-individual variation is small. Bad: Population variation is large: Creatinine varies by age, gender, and race (muscle mass) Protein intake, drugs, and exercise may also affect blood levels of creatinine. Bad?: Lacks sensitivity for early detection of declining renal function (Somewhat true, but is mgfr any better?). Is Serum Creatinine Not a Good Indicator of Early Changes in GFR? Is mgfr any better? Plot of Serum Creatinine vs GFR by Inulin Clearance From Figure 1 in: Botev R, et al. Clin J Am Soc Nephrol 29; 4: Page 4

5 Plot of Serum Creatinine vs GFR by Inulin Clearance CREATININE] mg/dl or umol/l From Figure 1 in: Clin J Am Soc Nephrol 29; 4: mg/dl scale makes Sensitivity appear much better! Iothalamate GFR vs Creatinine (log scale) in Polycystic Ovary Disease J Am Soc Nephrol 26; 17: DGFR % DCreat = = +6% What Was the MDRD Study and How was the MDRD egfr Equation Determined? Only adult patients (>18 yo) with chronic kidney disease were studied. Study included ~35 patients (proportional blacks : whites) with GFR < 9 ml/min/1.73m 2. GFR determined by iothalamate clearance (gold standard) was compared to creatinine and creatinine clearance. For several reasons, numerical MDRD egfr reported only when less than 6 ml/min/1.73m 2. Should all values of egfr be reported? Page 5 5

6 6 Old and New egfr Equations for Predicting GFR In Adults Cockcroft-Gault Equation (Nephron 1976;16:31): GFR = (14 - age) x Weight 72 x S Cr x.85 (if female) Abbreviated MDRD Equation (Ann Intern Med 1999;13:461): egfr = 186 x (S Cr ) x (Age) -.2 x (.742 if female) x (1.21 if black) egfr (IDMS) = 175 x (S Cr ) x (Age) -.2 x (.742 if female) x (1.21 if black) The new CKD-EPI equation (Ann Intern Med 29;15:64): egfr = 141 x min(s Cr /k,1) a x max(s Cr /k,1) x (.99) Age x (1.18 if female) x (1.16 if black) Conclusion: The egfr is a normalized creatinine that has been mathematically manipulated to have a numerical value resembling measured GFR. How Will the New CKD-EPI egfrs Differ From Other egfrs? Page 6

7 egfr (ml/min/1.7 m 2 ) egfr (ml/min/1.7 m 2 ) egfr (ml/min/1.7 m 2 ) 7 egfr: MDRD, IDMS, CKD-EPI, C-G: 7 yr old black male; 18 lbs MDRD MDRD-IDMS CKD-EPI C-G Creatinine (mg/dl) egfr: MDRD, IDMS, CKD-EPI, C-G: 4 yr old white male; 18 lbs MDRD MDRD-IDMS CKD-EPI C-G Creatinine (mg/dl) egfr: MDRD, IDMS, CKD-EPI, C-G: 7 yr old white female; 13 lbs MDRD MDRD-IDMS CKD-EPI C-G Creatinine (mg/dl) Page 7

8 Peer group mean bias vs. IDMS, mg/dl 8 Why Was Standardization of Creatinine Methods to an IDMS Definitive Method Necessary? Measurement of mg/dl (78 umol/l) (Study from 23) VERTICAL BARS = ±1.96xSD distribution of participant results Alk Picrate End Point Alk Picrate Kinetic Enzymatic Instrument/method peer group Miller et al. Arch Pathol Lab Med 25;129: = Abbott 2 = Siemens 3 = Beckman 4 = Dade 5 = Nova 6 = Olympus 7 = Roche 8 = Schpreli 9 = Toshiba = Vitros Benefits of Creatinine Standardization to IDMS Reference Method IDMS standardization will modestly improve agreement between creatinine methods. However, it will have no effect on: The differences between methods due to imprecision or interferences. the inherent variation between measured GFR and egfr calculated from serum creatinine. The variables of manufacturing calibrators and reagents over time. Page 8

9 9 Relative Precision of Chemistry Analyzers Means* and SD of Differences Between Duplicates (Creatinine concentration range ~ mg/dl) Large Chemistry Analyzer Dates Sum of Mean D (mg/dl) (mean of 9 duplicates) SD of D (mg/dl) (SD of 9 duplicates) Brand A Brand B Brand C Nov, Jan, March Nov, Jan, March Nov, Jan, March *Each mean and SD is calculated from the mean of 9 differences between same sample run on duplicate analyzers. Do ANY Equations Provide an egfr (from Creatinine) that Accurately Predicts GFR? Plots of Inulin GFR vs C-G egfr and MDRD egfr From Figure 2 in: Botev R, et al. Clin J Am Soc Nephrol 29; 4: Page 9

10 1 84.1% agree within 3% Performance of the CKD-EPI and MDRD Study equations in estimating measured GFR in the external validation data set. Both panels show the difference between measured and estimated versus estimated GFR 8.6% agree within 3% 29 by American College of Physicians Why the Variability in GFR by Clearance Measurements (Creatinine, Iothalamate, etc)? Incomplete voiding. That s why ultrasound and catheters are sometimes used to ensure bladder is empty. Variation or interference to urine (creatinine, iothalamate) measurement: 2 fold dilution for urine creatinine. GFR and egfr are very different paramaters: GFR is physiologically much more variable than serum creatinine! My Conclusion: GFR and Serum Creatinine Have Inherently Different Regulation Patterns 2 Relative % Change 1-1 ser Creat GFR Hour of Day Page 1

11 Serum Creatinine (mg/dl) 11 Within-Individual Variation (%CV) of Renal Function Tests on 31 Healthy Persons (Clin Chim Acta 28; 395: 115-9) Mean W-I variation = Range of W-I variations = + 2SD of W-I variations = % % % % Serum Creatinine (mg/dl) Serum Cystatin C (mg/l) Creatinine Clearance GFR (ml/min/1.7m 2 ) egfr (MDRD) (ml/min/1.7m 2 ) Does Eating Meat Affect Plasma Creatinine? Changes in Serum Creatinine Pre/Post Meat Ingestion: Duplicate Picrate and Triplicate Enzymatic Measurements (1 person!) Picr Creat 1 Picr Creat 2 Enz Creat 1 Enz Creat 2 Enz Creat Meat eaten 1 hr Pre hr Pre 1 hr post 2 hr post 4 hr post Page 11

12 12 Plasma Creatinine is Frequently Criticized for Having a Large Population Variation. However: GFR Also Has a Large Population Variation (in addition to a large within-individual variation). Both Creatinine and GFR Vary in Health Parameter Serum creatinine (mg/dl) Healthy Persons (n = 51) Mean + 2 SD Range Iothalamate GFR (ml/min/1.73 m 2) Ann Intern Med 24; 141: GFR Varies by Age Age (years) Average GFR (ml/min/1.73 m 2 ) Page 12

13 13 GFR vs Stage of Chronic Kidney Disease: Some Recent Changes New stages: 3a: b: 3-44 New Albuminuria Categories: A1: <3 mg/g A2: 3-3 A3: >3 CKD Description Stage 1 Kidney damage with normal GFR 2 Kidney damage with mild GFR GFR (ml/min/1.73m 2 ) > Moderate GFR Severe GFR Kidney failure < 15 (or dialysis) Clin Chem 213; 59: Normal Range for GFR is Reportable Range for MDRD egfr A Few Notes on Cystatin C Originally reported to have much smaller population variation than serum creatinine, this does not appear to be true: Both within-individual and between-individual variations were slightly larger for cystatin C than for creatinine:» Scand J Clin Lab Invest 29; 69: (adults)» Scand J Clin Lab Invest 21; 7: (children) Both studies concluded that serum creatinine would be better for serial monitoring of renal function. Cystatin C Does Appear to be Clinically Useful Recommended to confirm CKD when egfr is ml/min/1.7m 2. Is a better predictor of mortality in patients with CKD, HF, or CVD. Among 442 general ICU patients, cys C indicated acute kidney injury earlier than did serum creatinine: In 342 pts, neither increased In 17 pts, creat increased before cys C In 66 pts, cys C increased before creat In 17 pts, both increased at same time Page 13

14 egfr mgfr (ml/min/1.7 m 2 ) 14 Comparisons of Cystatin C egfr Equations to Measured GFR Individual errors (egfr mgfr) of the CAPA and CKD-EPI cystatin C equations at different levels of mgfr. A and B are Swedish adults, C is Japanese adults, n = 763. (Clin Chem 214; 6:7: ) Some Conclusions Within-individual changes in serum creatinine should rival or surpass GFR for indicating early changes in renal function. Three recent reports in Clin Chem support clinical value of serum creatinine: Clin Chem 21; 56: (pages 687, 74, and 799) Can we report creatinine to nearest.1 mg/dl, or 1 umol/l? IDMS standardization will improve agreement between creatinine methods. However, it will have no effect on: The differences between methods due to imprecision, calibration variation, reagent variation, or interferences. the inherent variation between measured GFR and egfr. Physiologic parameters (ie, GFR, cardiac output) are often not optimal markers for detecting disease. If egfr is Here to Stay, What is It s Future? Will reporting all egfr values improve clinical interpretation? The CKD-EPI may allow this. Need to develop specific guidelines for interpreting egfr, independent of the mgfr: correlate egfr with clinical findings: scr, mgfr, Alb ur, cystatin C, urinalysis, histology, etc. Develop predictive values for egfr. Emphasize value of serial measurements: Both of creatinine and egfr! What analytical change represents a real physiologic change? Page 14

15 15 GLOMERULAR FILTRATION RATE IN CLINICAL PRACTICE ABUSUS NON TOLLIT USUM MISUSE DOES NOT REMOVE USE Rossini C. Botev, M.D., FASN Hawaii Permanente Medical Group Assistant Clinical Professor of Medicine, University of Hawai i at Manoa Learning Objectives What is presently known and not known regarding normal GFR according to age The rational of adjusting GFR for body surface area and its limitations when applied to different adult populations Deciphering the statistics used to evaluate and compare the performance of estimated GFR (egfr) formulas Benefits and pitfalls when ordering simply a serum creatinine, but the laboratory also reports automatically the egfr Learning Objectives What is presently known and not known regarding normal GFR according to age The rational of adjusting GFR for body surface area and its limitations when applied to different adult populations Deciphering the statistics used to evaluate and compare the performance of estimated GFR (egfr) formulas Benefits and pitfalls when ordering simply a serum creatinine, but the laboratory also reports automatically the egfr Page 15

16 Davies and Shock data hock data 16 Age Related Decline of GFR * Mean GFR in normal men based on linear regression GFR= (age) ** Assumes that values for women are 8% lower at all ages. GFR measured by inulin clearance. Data abstracted from: Davies DF, Shock NW: J Clin Invest 195, 29: Watkins DM, Shock NW: J Clin Invest 1955, 4:969 K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification. Am J Kidney Dis 39:S1-S266, 22 (suppl 1) Age and Gender Related Decline of GFR Inulin urinary clearance GFR by age for normal men (a) and women (b) Solid lines are mean value and dashed lines are 1 SD. Wesson L. Physiology of the Human Kidney. Grune & Stratton: New York, KDIGO 212 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney inter., Suppl. 213; 3: 1 15 Age and Gender Related Decline of GFR 51 Cr-EDTA (15 studies, one by 99m Tc-DTPA) GFR by age in 1878 healthy kidney donors. Mean GFR 96 ±16 vs 88 ±16 ml/min/1.73m2, p<.1, for men vs women Age related decline.8 vs.6 mi/min/1.73m2 per year for women vs men Peters AM et al. Nephrol Dial Transplant 27: , 212 Page 16

17 17 Age Related Decline of GFR 6 Non-radiolabeled iothalamate GFR by age in 365 kidney donors. Mean GFR at age of 2 years ml/min/1.73m 2 Age related GFR decline of 4.9 ml/min/1.73m 2 per decade. Rule AD, et al, Am J Kidney Dis 24, 43: Age and Gender Related Decline of GFR 125I-iothalamate urinary clearance mgfr by age in 157 kidney donors Mean GFR women vs men: 19 ±17.5 vs 16 ±15.8 ml/min/1.73m 2, P<.15 Age related GFR decline of 3.7 (age<45) and 7.5 (age>45) ml/min/1.73m 2 per decade Poggio ED, Rule AD, et al. Kidney International 29, 75: Age and Gender Related Decline of GFR Poggio ED, Rule AD, et al. Kidney International 29, 75: Page 17

18 Age and Gender Related Decline of GFR egfr by the re-expressed MDRD equation in kidney donors (black lines) and in selfreferred healthy subjects participating in the Nijmegen study (gray lines) Poggio ED, Rule AD, et al. Kidney International 29, 75: Age Related Decline of GFR egfr by MDRD in community based US population (NHANES III) vs mgfr by inulin clearance in 7 healthy men K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification. Am J Kidney Dis 39:S1-S266, 22 (suppl 1) Learning Objectives What is presently known and not known regarding normal GFR according to age The rational of adjusting GFR for body surface area and its limitations when applied to different adult populations Deciphering the statistics used to evaluate and compare the performance of estimated GFR (egfr) formulas Benefits and pitfalls when ordering simply a serum creatinine, but the laboratory also reports automatically the egfr Page 18 18

19 GFR, ml/min GFR, ml/min/1.73m2 GFR Indexing for BSA Jones GR. Clin Biochem Rev. 211, 32(2): Mathematical Prerequisites for the BSA Use in GFR Indexing Delanaye P, at al. Nephrol Dial Transplant 29, 24: GFR Indexing for BSA Relation between BSA and unadjusted GFR Relation between BSA and adjusted GFR for BSA BSA, m BSA, m2 Slides created from data for 228 inulin mgfrs published in: Botev R, et al. Clin J Am Soc Nephrol 29, 4: Page 19 19

20 2 GFR Indexing for BSA Overweight Control P value Age (y) 43.3 ± ± 1.67 NS Height (m) 1.62 ± ±.2 NS Weight (kg) 122 ± ± BMI (kg/m 2 ) 46.8 ± ±.93.1 BSA (m 2 ) 2.18 ± ±.4.1 Waist/hip ratio 1.9 ±.3.88 ±.3.1 Lean body weight (kg) 54.2 ± ± NS Creatinine (mg/dl ).95 ±.1.95 ±.2 NS Glucose (mg/dl) 83.5 ± ± 4.4 NS SBP (mm Hg) ± ± 2.21 NS DBP (mm Hg) 85.4 ± ± 1.36 NS GFR (ml/min) 16.6 ± ± 1.8 NS GFR (ml/min/1.73m 2 ) 84.1 ± ± The patients were normotensive and without microalbuminuria Lean body weight calculated by bioelectrical impedance analysis. Anastasio P, et al. Am J Kidney Dis 2 35(6): GFR Indexing for BSA Anastasio P, et al. Am J Kidney Dis 2 35(6): White Male - case # 1 MDRD and CKD-EPI vs. Cockcroft-Gault Wt 61 kgs(134 lbs), Ht 5 8, BSA 1.73 m 2, BMI 2, SCr 1.2 mg/dl White Female - case # 2 Wt 66 kgs(145 lbs), Ht 5 5, BSA 1.73 m 2, BMI 24, SCr 1.2 mg/dl White Male - case # 3 Wt 68 kgs(149 lbs), Ht 5 4, BSA 1.73 m 2, BMI 26, SCr 1.2 mg/dl White Female - case # 4 Wt 74 kgs(163 lbs), Ht 5 1, BSA 1.73 m 2, BMI 31, SCr 1.2 mg/dl Case # Age MDRD (BSA) CKD-EPI (BSA) C - G (Wt) Page 2

21 21 Case Presentation Nephrology CKD Latest Ref Rng 1/27/29 1/28/29 12/11/29 12/2/29 BP - Off Visit 112/7 Weight 198 lbs GFR Creat mg/dl 1.4 (H) 1.5 (H) BUN 8-2 mg/dl 11 FBS 7-99 mg/dl 96 24hr Urine Prot 4-15 mg 128 Creat 24Hr Urine gm 2.56 Nephrology CKD Latest Ref Rng 7/19/212 7/19/212 3/19/213 6/13/214 BP - Off Visit 126/72 17/62 Weight 193 lbs 185 lbs GFR Creat mg/dl 1.3 (H) 1.3 (H) BUN 8-2 mg/dl 15 FBS 7-99 mg/dl HgbA1C <5.7 % 5.5 Case Presentation 1/27/9 SCr 1.4 Ht 1.9m (6 3 ), Wt 9 kgs (198 lbs), BMI 25, BSA 2.18 MDRD 55 ml/min/1.73 m 2 69 ml/min CKDEPI 61 ml/min/1.73 m 2 77 ml/min CG 87 ml/min 6/13/14 SCr 1.3 Ht 1.9m (6 3 ), Wt 84 kgs (185 lbs), BMI 23, BSA 2.11 MDRD 59 ml/min/1.73 m 2 72 ml/min CKDEPI 65 ml/min/1.73 m 2 79 ml/min CG 83 ml/min Examine the Patient to Make a Diagnosis Page 21

22 22 Learning Objectives What is presently known and not known regarding normal GFR according to age The rational of adjusting GFR for body surface area and its limitations when applied to different adult populations Deciphering the statistics used to evaluate and compare the performance of estimated GFR (egfr) formulas Benefits and pitfalls when ordering simply a serum creatinine, but the laboratory also reports automatically the egfr Deciphering the Statistics Used to Compare the Performance of egfr Formulas Correlation (r ) and variability (r 2 ) coefficients express only the linear association and common variance but not the difference between two variables (egfr and mgfr) Bias, as a mean or median difference between egfrs and mgfrs, reveals clinically whether overall the egfr formula under- or over-estimates the mgfr Precision, as a SD of mean bias or an interquartile range (25 th to 75 th percentile) of median bias, represents the spread of egfrs around the mgfrs Accuracy, as a percentage of the distribution of egfrs within particular range around their respective mgfrs, combines bias (systemic deviation) and precision (dispersion) P values mgfr and egfr in 274 potential kidney donors A. Cockcroft-Gault equation compared with mgfr r =.35; P <.1 B. MDRD equation compared with mgfr r =.26; P <.1 Rule AD, et al. Am J Kidney Dis 24, 43: Page 22

23 r, Correlation coefficient - Association r 2, Variability coefficient - Variance Simultaneously measured GFRs by urinary clearances of intravenous infusion of inulin (Cin) and subcutaneous injection or intravenous infusion of 125I-iothalamate (Cio) in 94 subjects. Botev R, et al. Clin J Am Soc Nephrol 211, 6: Bias - Difference by Bland-Altman Analysis Simultaneously measured GFRs by urinary clearances of intravenous infusion of inulin (Cin) and subcutaneous injection or intravenous infusion of 125I-iothalamate (Cio) in 94 subjects. Botev R, et al. Clin J Am Soc Nephrol 211, 6: Relative Bias Percentage Difference Simultaneously measured GFRs by urinary clearances of intravenous infusion of inulin (Cin) and subcutaneous injection or intravenous infusion of 125I-iothalamate (Cio) in 94 subjects. Botev R, et al. Clin J Am Soc Nephrol 211, 6: Page 23 23

24 Number of Cio witin range of respective Cin, % 24 Accuracy - Percentage Distribution Within Particular Percentage Range 1 9% 75 63% 5 44% Range groups, % Simultaneously measured GFRs by urinary clearances of intravenous infusion of inulin (Cin) and subcutaneous injection or intravenous infusion of 125I-iothalamate (Cio) in 94 subjects. Botev R, et al. Clin J Am Soc Nephrol 211,6: Accuracy There is no agreement on what percentage range to be used In the KDOQI guidelines, a range of ±3% with 9% of egfrs within this range, was cited as a useful measure of accuracy Accuracy range within 3% is too wide at mgfr of 6 ml/min/1.73 m 2, i.e. egfr range of ml/min/1.73 m 2, to be useful in clinical practice Day-to-day mgfr variation was reported to be as high as 17%, hence accuracy within 15% is much more useful Botev R, et al. Clin J Am Soc Nephrol 211,6: Gold Standard for Measured GFR The 24-carat gold and 22, 18,14, etc. carats of gold Reference test - renal inulin clearance, index and reference measurements were conducted within 48 hours Soveri I, et al. Am J Kidney Dis. 214 May 17 [Epub ahead of print] Page 24

25 25 CG vs MDRD vs CKD-EPI CG MDRD Accuracy - within 3% (%) Bias - mean difference (ml/min/1.73m 2 ) CKD - proper staging (%) Data based on review of 9 publications. Botev R, et al. Clin J Am Soc Nephrol 29, 4: CG MDRD CKD-EPI Accuracy - within 3% (%) Bias - mean difference (ml/min/1.73m 2 ) Data based on review of 11 publications. Delanaye P, Pottel H, Botev R. Nephrol Dial Transplant 213, 28: MDRD vs CKD-EPI Accuracy Within 3% Within 15% MDRD CKD-EPI MDRD CKD-EPI Overall GFR> GFR GFR Bias Precision Mean Median SD of Mean MDRD CKD-EPI MDRD CKD-EPI MDRD CKD-EPI Overall GFR> Data presented as calculated weighted average, based on review of 26 publications: Delanaye P, Pottel H, Botev R. Nephrol Dial Transplant 213, 28: MDRD vs CKD-EPI Absolute Bias Levey AS et al. Ann Intern Med. 29;15: Page 25

26 MDRD, % difference CKD-EPI, % difference 26 MDRD vs CKD-EPI Absolute Bias MDRD - Cin, ml/min/1.73m CKD-EPI - Cin, ml/min/1.73m Cin GFR, ml/min/1.73m 2 Cin GFR, ml/min/1.73m 2 Botev R et al. Unpublished data MDRD vs CKD-EPI Relative Bias Cin GFR, ml/min/1.73m Cin GFR, ml/min/1.73m 2 Botev R et al. Unpublished data CKD-EPIcr vs CKD-EPIcys vs CKD-EPIcr+cys Inker LA et al. N Engl J Med 212;367:2-9. Accuracy - percentage of estimates that differed from measured GFR by more than 3% (1 P3) Page 26

27 CKD Classification Performance The most important statistical tool for the clinicians to evaluate an equation s performance on individual level The percentage of patients correctly classified by egfr into the different CKD stages in comparison with the confirmatory test of mgfr CG and MDRD formulas correctly classified overall only 64% and 62%, respectively, of the patients in a review article. CKD-EPI formula correctly classified overall only 69% and 64% of the patients in two recent studies Approximately 1 million (38% of 26.3 million) by MDRD and million (31-36% of 23.2 million) by CKD-EPI subjects might be misclassified (based on the respective estimated CKD prevalence in USA) Botev R, et al. Clin J Am Soc Nephrol 211, 6: Bjork J, et al. Scand J Urol Nephrol 212; 46: Masson I, et al. Transplantation 213 Mar 18. [Epub ahead of print] Learning Objectives What is presently known and not known regarding normal GFR according to age The rational of adjusting GFR for body surface area and its limitations when applied to different adult populations Deciphering the statistics used to evaluate and compare the performance of estimated GFR (egfr) formulas Benefits and pitfalls when ordering simply a serum creatinine, but the laboratory also reports automatically the egfr Current Outstanding Issues Diagnosing CKD Only by GFR All GFR cut-off levels used for CKD diagnosis and staging are arbitrary: the cut-off levels between stages are inherently arbitrary. A GFR<6 ml/min/1.73m 2 is labeled as CKD but normal GFR varies with age and gender. For men, normal renal inulin GFR range (1 SD) is ml/min/1.73m 2 at age 2-29 years, down to 46-7 ml/min/1.73m 2 at age 8-89 years. Hence, there is under-diagnosing of young and over-diagnosing of elderly subjects with CKD The laboratory report for egfr should include normal GFR range by age in order to prevent underor over-diagnosing of CKD Page 27 27

28 Current Outstanding Issues Diagnosing CKD Only by GFR In obese subjects, the GFR correction to BSA of 1.73m 2 lowers the actual GFR value artificially. This is another source of CKD overdiagnosing in view of the estimated 27% prevalence of obesity in USA. State-specific prevalence of obesity among adults: United States, 29. MMWR 59: 1 5,21 Accessed August 6, 21 Current Outstanding Issues Diagnosing CKD Only by GFR There is limited data for normal GFR range at age>75 years, a 18.5 million U.S. population in 21. The prevalence of estimated GFR<6 ml/min/1.73m 2 was 37.8% for age>7 years ( NHANES survey). More studies are needed to establish normal GFR range for age>7 years because millions of elderly might be misdiagnosed with CKD. Current Outstanding Issues Diagnosing CKD Only by GFR The available data for age>7 years are mgfr by renal inulin clearance but the endorsed MDRD and CKD-EPI equations are based on mgfr by renal 135-iothalamate clearance. There is a significant difference between the inulin by continous infusion and 135-iothalamate by subcutenous injection GFRs when simultaneously measured. mgfr calibration is needed (as SCr calibration was done already), i.e. correlation coefficients between inulin and other mgfr methods as iothalamate, iohexol, DTPA, and EDTA. Page 28 28

29 29 Point Prevalent Distribution and Annual Costs of Medicare Populations estimated from the 5 percent Medicare sample using a point prevalent model Population further restricted to patients age 65 & older, without ESRD Diabetes, CHF, & CKD determined from claims. Costs are for calendar year 21. USRDS 212 ADR Cost of CKD Estimated cost per patient labeled with CKD at age>65 years was $2,432 in 28 and up by 1% to $22,323 in 21 Minimum estimated cost for CKD in USA was $37.5 billions, as per data in the USRDS 211 report. Undoubtedly, there are very significant financial implications related to the current CKD classification s outstanding issues. Page 29