Εκηίμηζη ηης μεθρικής λειηοσργίας Ε. Μωραλίδης

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1 Εκηίμηζη ηης μεθρικής λειηοσργίας Ε. Μωραλίδης Ιατρική Σχολή ΑΠΘ Νοσοκομείο ΑΧΕΠA Θεσσαλομίκη

2 Kidney in body homeostasis Excretory function Uremic toxins removal Vascular volume maintainance Fluid-electrolyte balance Endocrine function Renin Vitamin D Erythropoietin Acid-base balance

3 Operational renal function Glomerular Filration Rate (GFR) is accepted as the best index for the complex functions of the kidney GFR attributes Functional: glomero-tubular coupling Pathological: correlates with interstitial fibrosis and tubular atrophy in chronic kidney disease Prognostic: predicts the onset of kidney failure and the risk of complications in chronic kidney disease

4 Chronic kidney disease K/DOQI Clinical Practice Guidelines KDIGO Position Statement 2005 Definition Staging ml/min/1.73m 2 Structural or functional abnormalities of the kidneys for 3mo, irrelevant of GFR, but that may lead to GFR decline, manifested by Pathology Markers of kidney damage (blood, urine, imaging tests) GFR 60 ml/min/1.73m 2, with or without kidney damage 1 Kidney damage with normal or increased GFR 90 2 Mild decrease in GFR Moderate decrease in GFR Severe decrease in GFR Kidney failure 15

5 GFR in kidney failure and cardiovascular risk KDIGO Position Statement 2005 Risk CKD stage

6 Likelihood of Diabetic Kidney Disease KDOQI Guidelines for Diabetes and Chronic Kidney Disease 2007 GFR (ml/min) Albuminuria Normo- Micro- Macro- 60 at risk possible definite unlikely possible definite 30 unlikely unlikely definite

7 GFR in DM patients Nowack R. Am Kidney Dis 1992;20: Hyperfiltration (increased GFR) is the earliest demonstrable effect of diabetes on the kidney Caramori ML. Diabetes 2003;52: Significant glomerular changes may occur in normoalbuminuric DM patients with decreased GFR Herlitz H. Scand J Urol Nephrol 1983;17: Normal kidneys remove 1/3 of insulin in the blood Parving HH. Diabetes Care 2002;25: Diabetics with GFR 60 ml/min/1.73m 2 are at risk to develop hyporeninemic hypoaldosteronism

8 GFR assessment in clinical practice Substances Measurement (clearance) Models Estimation (formulas) Endogenous Exogenous creatinine urea cystatin C Chemicals inulin Infusion with timed urine & plasma samples Radionuclides 51 Cr-EDTA 99m Tc-DTPA 125 I-iothalamate Bolus with plasma urine collections Cockroft-Gault MDRD CKD-EPI Mean urea & creatinine clearance Contrast media iohexol

9 Clearance and GFR Clearance GFR The imaginary plasma flow which is totally cleared from a tracer C = U x V / P V, urinary flow U & P, urinary and plasma concentrations E, renal extraction F, plasma flow C = E x F Tracer Freely filtered Inert Without protein binding Not secreted Not reabsorbed C = Q / 0 P Q, quantity of administered tracer 0 P, integral of plasmatic concentration over time

10 Inulin Homer Smith, 1930 Polysaccharide Ideal characteristics Urinary clearance Levey AS, Semin Nephrol 1989;9:370-9 Within day CV 10% Between day CV 7.5% Plasma disappearance Scarce, costly, cumbersome techniques

11 Iohexol Nonionic, low osmolar contrast medium Low-dose (eg 10 ml) HPLC, X-ray fluorescence Good correlation between plasma clearance of iohexol and that of Inulin 51 Cr-EDTA 99m Tc-DTPA Used in Northern Europe

12 51 Cr-EDTA plasma clearance Q C = Q / 0 P Q, quantity of administered tracer 0 P, integral of plasmatic concentration over time

13 51 Cr-EDTA plasma clearance

14 51 Cr-EDTA plasma clearance Highly accurate and precise GFR determination Day-to-day CV 6% 10 ml/min/1.73m 2 difference is clinically significant Patient examined (a) after a low-protein breakfast, (b) adequately hydrated and (c) relaxed Single iv injection and blood sampling at 2-4 hrs Low-moderate cost Negligible radiation exposure (0.01 msv)

15 Serum creatinine Derived form creatine in skeletal muscles Constant release, steady plasma concentration Freely filtered, but up to 20% in urine from tubular excretion In picric-acid Jaffé reaction 20-30% non-creatinine chromogens relative to HPLC or mass spectrometry Modified kinetic Jaffé reaction and enzymatic methods which can be calibrated to avoid non-creatinine chromogens

16 Serum creatinine Ross JW, Arch Pathol Lab Med 1998;122: College of the American Pathology survey of 700 laboratories: Overestimation of SCr 13-17% Considerable interlab variation 85% of SCr variation was due to different calibration Miller WG, Arch Pathol Lab Med 2005;129: College of the American Pathology survey of 5624 laboratories: Significant bias due to instrument manufacturer rather than analytic methodologies Miller WG, Arch Pathol Lab Med 2005;129: NIH National Kidney Dis Education Program Recommendation Laboratories should calibrate SCr measurements to the Cleveland Clinic Lab standard (MDRD).

17 Serum creatinine Botev R, Clin J Am Soc Nephrol 2009;4:

18 Creatinine clearance Urinary creatinine approximates endogenous production according to muscle mass, age, gender and ethnicity Major sources of error Incomplete urine collection Increasing tubular secretion of creatinine in GFR Walser M, Am J Kidney Dis 1998;32:23-31 Day-to-day CV up to 27% K/DOQI Clinical Practice Guidelines 2002 Cl Cr is no longer suggested as an estimate of GFR

19 Creatinine clearance vs prediction equations K/DOQI Clinical Practice Guidelines 2002 Predictive equations were more reliable estimates

20 Prediction equations Adults Cockroft-Gault 1976 (ml/min) Cl Cr = [ (140 age) x weight / Scr x 72 ] (x 0.85 if female) 4v-MDRD 2005 (ml/min/1.73m 2 ) GFR = 175 x SCr x age (x if female) (x if African American) Children Schwartz 1976 (ml/min) Cl Cr = 0.55 x length / Scr Counahan-Barrat 1976 (ml/min/1.73m 2 ) GFR = 0.43 x length / SCr

21 Prediction equations -MDRD Study Population n marker GFR mean SCr calibration Results Bias A 30 Lewis 2001 Nephrosclerosis I-iothalamate 57 Yes -3% 88 Rule 2004 CKD Kidney donors Iothalamate No -6% -29% Gonwa 2004 Pre-liver Tx 3 mo post Tx 1 yr post Tx 5 yrs post Tx I-iothalamate No Poggio 2005 CKD-diabetes CKD-no diabetes Kidney donors I-iothalamate Yes 1% -4% -9% Froissart Cr-EDTA 61 Yes Ibrahim 2005 T1DM in DDCT I-iothalamate 122 No Verhave 2005 CVD risk screening m Tc-DTPA 99 No

22 Prediction equations C-G and MDRD Coresh J, Stevens AL. Curr Opin Nephrol Hypertens 2006;15: In people with CKD or patients with low GFR the MDRD equation outperforms Cockroft-Gault formula Both equations are superior to SCr alone Calibrated creatinine allows better performance Both equations are less accurate in predicting higher GFR values underestimation with MDRD age and weight affected with Cockroft-Gault

23 Prediction equations CKD-EPI Levey AS, Ann Intern Med 2009;150: White Female SCr 0.7 mg/dl GFR = 144 x (SCr/0.7) x Age SCr 0.7 mg/dl GFR = 144 x (SCr/0.7) x Age Male SCr 0.9 mg/dl GFR = 141 x (SCr/0.7) x Age SCr 0.9 mg/dl GFR = 141 x (SCr/0.7) x Age

24 Prediction equations Levey AS, Stevens AL. Am J Kidney Dis 2010;55: Cockroft-Gault MDRD CKD-EPI No 249 1,628 5,504 Age (years) Sex (% male) mgfr (mean) Reference standard Cl Cr Cl Cr or 125 I-iothalamate Cl Cr or 125 I-iothalamate Standardized SCr No Yes (2006) Yes Diabetes NR 6% 29% Validation Many studies Many studies Appearing

25 Prediction equations Levey AS, Stevens AL. Am J Kidney Dis 2010;55: Cockroft-Gault MDRD CKD-EPI Bias Overestimation of mgfr Underestimation of mgfr Lesser bias than C-G Underestimation of mgfr Lesser bias than MDRD Precision Limited Greater than C-G; still limited Greater than MDRD; still limited egfr reporting Limited Applicable in GFR 60 Applicable throughout egfr range (?) CKD prevalence than MDRD 13% in US than MDRD Prognosis Difficult to relate to CKD stage Uncertain for CKD stage 3a More accurate for CKD stage 3a Treatment Drug dosing Drug dosing proposed Drug dosing proposed

26 GFR estimation and measurement Giles PD, BMJ 2007;334: Froissart M, J Am Soc Nephrol 2005;16:

27 GFR measurement over estimation Unreliable GFR estimation Extremes of age Grossly abnormal muscle mass (paralysis, muscle disease, amputation, obesity, malnutrition, BMI 18.5kg/m 2 ) High or low intake of creatine (dietary supplements, vegeterians) Rapidly changing renal function Pregnancy High accuracy is needed Kidney donation Prior to dosing toxic drugs excreted by the kidneys High-risk patients: diabetes, hypertension, etc Follow-up in CKD (rate of progression) Clinical research with GFR as primary end-point

28 Cystatin C Prigent A, Sem Nucl Med 2008;38:32-46 Member of cysteine proteinase inhibitors Produced in a constant rate by all nucleated cells Controls extracellular proteolysis and modulates the immune system Freely filtered by the glomerulus, almost entirely reabsorbed and catabolized by proximal tubules Ideal endogenous substance to detect mild GFR changes (pediatric populations and diabetics)?

29 Cystatin C Prigent A, Sem Nucl Med 2008;38:32-46 Intra-individual variance up to 75% vs 7% for SCr Its levels affected by a number of factors (age, men, body mass, smoking, glucocorticoids, CRP, malignancy) formulas No clear evidence that multi-variate cystatin C estimates are superior to SCr based equations Increased cost

30 Renography and kidney function Man, 64 yrs, T2DM, 112 kg, 192 cm SCr = 1.2 mg/dl C-G = 69 ml/min/1.73m 2 MDRD = 65 ml/min/1.73m 2 CDK-EPI = 64 ml/min/1.73m 2 GFR = 42 ml/min/1.73m 2

31 GFR estimation in T2DM patients Iliadis F, Diabetologia 2011, doi: /s Variable Total GFR (ml/min/1.73m 2 ) N Age (yrs) SCr (mg/dl) Bias A 30 A 10 Bias A 30 Bias A 30 Bias A 30 A 10 MDRD CKD-EPI Tan-C

32 GFR assessment 51 Cr-EDTA provides an optimal assessment of GFR and it is suitable for the investigation of diabetic patients Prediction equations are a significant step forward for the determination of renal function Calibration of SCr measurements (IDMS traceable) is recommended and the limitations of prediction equations should be realized in clinical implementation KDIGO Position Statement 2005 Creatinine clearance may be a useful alternative when exogenous filtration markers are not available

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