Nephrologists. from. All physicians Patients Health care system Policy makers World health leaders Researchers. Clinical laboratories

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1 Creatinine standardization The most important expectation of Nephrologists All physicians Patients Health care system Policy makers World health leaders Researchers Drug manufacturer Clinical laboratories from Iranian laboratory system

2 In modern medicine LAB TESTS AS DOUBLE-EDGED EDGED SWORD

3 An example : One recent study in the United States: laboratory calibration errors that affect the accuracy of calcium test results is costing $66 to $199 million dollars per year as a result of the costs of the clinical decisions that were made in response to the inaccurate calcium li test results Downer K: How much does test calibration error cost? NIST report suggests $60-$199M for calcium testing alone. Clin Lab News 30(4): 1, 8 9, 2004

4 NONCOMMUNICABLE DISEASE IS THE PROBLEM OF DEVELOPED AND DEVELOPING COUNTRIES

6 Chronic kidney disease (CKD) is a worldwide public health problem Number of end-stage renal disease (ESRD) Medicare-funded e e patients ts in US: From 86,354 in 1983, to 547,982 as of 2008 Medicare costs per person per year is $66,000 The estimated number of people with earlier stages of CKD is 19 million

8 Overall prevalence of CKD stages 1 through 5 is 14.2 percent (US data) 1.8 percent 3.2 percent 7.7 percent 0.35 percent 2.4 percent

9 IRAN CKD STATISTICS

10 پيشگيری از بيماری ھای کليوی در ایران موجود پيشگيری از ابيماریھای وضع کليه در ایران شناسایی مشکل : شيوع مشابه کشور ھای پيشرفته رشد ساالنه 12 درصد در بيماران پيشرفته کليه یعنی سالی 4000 نفر یا 3 برابر شدن در ده سال افزایش بيماران به دليل زنده تلف شدن ساالنه افزایش نقش دیابت از حاضر در حال ماندنشان سال از عمر مردم 16 درصد در سال 1378 کشور 45 به در صدی 20 نقش فشار خون درصد

11 The growing number of patients with ESRD in IRAN

High prevalence of chronic kidney disease in

aged over 20 years, in Tehran, Iran Overall

12 High prevalence of chronic kidney disease in Iran: a large population-based study Farhad Hosseinpanah1, Farshad Kasraei1, Amir A Nassiri1 and Fereidoun Azizi participants aged over 20 years, in Tehran, Iran Overall prevalence of CKD with the abbreviated MDRD equation was 18.9%

13 J Nephrol 2009; 22(1): The epidemiology of adult chronic kidney disease in a population-based study in Iran: prevalence and associated risk factors Mohammad R. Safarinejad 17,240 persons of either sex over 14 years old from 30 counties of Iran 8% had GFR<60%

14 Prevalence of Chronic Kidney Disease and its Associated Risk Factors: The First Report from Iran Using Both Micro albuminuria and Urine Sediment Iraj Najafi, et al enrolled subjects in this study (8.89%) were categorized as CKD stages III-V 3591 participants ( 18 years old) Prevalence of CKD stages 3 to 5 (CKD S3-5), i.e., GFR <60 ml/min/1.73 m2, was 4.6%

15 A high serum creatinine level was considered 1.5 mg/dl or higher in men and 1.3 mg/dl or higher in women A high serum creatinine level was demonstrated in 343 participants p (37.9%),

16 Screening for decreased renal function in taxi drivers in Tehran, Iran. Mahdavi-MazdehMazdeh M, Saeed Hashemi Nazri S, Hajghasemi E, Nozari B, Zinat Nadia H, Mahdavi A. Source Department of Nephrology, Tehran University of Medical Sciences; Research Center of Iranian Tissue Bank, Tehran, Iran. The survey covered 31,999 taxi driver across Tehran Using the MDRD equation, overall prevalence of egfr <60 ml/min/1.73 m(2) was 6.5%

17 MANAGEMENT OF CRISIS

18 The main steps in CKD crisis management 1. Epidemiologic studies (Spec. in high risk groups) 2. Defining the burden of CKD 3. Classification and guideline development 4. Clinical researches 5. Comparative studies 6. Primary and secondary prevention

19 No Cr Std. = Fail to reach finish line

20 LABORATORY TESTS OF KIDNEY PROBLEMS

21 Creatinine and albumin in the urine

22 GFR TESTS AND FORMULAS

23 THE GFR and serum Creatinine

25 Gold standards tests for GFR mesearment The urinary clearance of the exogenous substance inulin is considered the gold standard method Radioisotopes such as iothalamate and other markers have replaced inulin in clinical laboratories These methods are expensive, time- consuming, and not widely available

26 ESTIMATING THE GFR(eGFR) Measuring 24-hour creatinine clearance Burdensome for the patient The results are not always reliable because of variations in collection technique Using the creatinine clearance does not resolve problems with using the serum creatinine concentration, such as tubular secretion and overestimation i of GFR. CCr = [urine creatinine (mg per dl) x urine volume (ml per 24 hour)] /[serum Cr (mg gp per dl) x 1, 440 minute]

27 The Cockcroft-Gault equation GFR = [([140 age (years)] x lean body weight in kg)/(serum Cr x 72)] x (0.85 if female) Its main drawbacks: It was developed to model creatinine It was developed to model creatinine clearance, itself an imperfect estimation of GFR It depends heavily on the accuracy of the value for lean body weight used in the equation.

28 MDRD Modified MDRD formula GFR, in ml per minute per 1.73 m = x(serumcr ) x (age ) x (0.742 if female) x (1.21 if black) The MDRD equation has now largely replaced the Cockcroft-Gault equation it is normalized to a standard body surface area (1.73 m2), obviating the need to determine ideal body weight can be reported directly with any laboratory report The main drawback of the MDRD equation is that it tends to underestimate GFR at higher ranges of kidney function, ie, higher than 60 ml/min/1.73 m 2 ) less accurate at racial and ethnic groups outside of North America, Europe, and Australia

The CKD-EPI equation The Chronic Kidney Disease Epidemiology Collaboration study (CKD-EPI) equation, (2009,) is expected to eventually replace the currently used MDRD equation,

29 The CKD-EPI equation The Chronic Kidney Disease Epidemiology Collaboration study (CKD-EPI) equation, (2009,) is expected to eventually replace the currently used MDRD equation, as it performs better at higher ranges of GFR It was developed with the objective of reporting a specific value even when the estimated GFR is greater than 60 ml/min/1.73 /1 m2

31 Schwartz and the Counahan Barratt equations For estimating GFR in children The MDRD contributes to substantial uncertainty in estimating GFR in children

32 MDRD or CKD-EPI Neither the CKD-EPI nor the MDRD Study equation is optimal for all populations p and GFR ranges A general practice and public health perspective p favors the CKD-EPI equation For nephrology practices and transplant patients the MDRD is better

33 egfr Reporting Estimates of glomerular filtration rate (GFR) from serum creatinine levels are now reported by more than 80% of clinical laboratories in the United States staging g chronic kidney disease determining drug dosages stratifying risk

34 TRUENESS OF CR PRECISION AND STANDARDISATION

Effect of creatinine measurement imprecision on estimated GFR 2003 CAP survey- Miller WG Myers GL Ashwood ER Killeen AA Wang E Thienpont LM et 2003 CAP survey- Miller WG, Myers

35 Effect of creatinine measurement imprecision on estimated GFR 2003 CAP survey- Miller WG Myers GL Ashwood ER Killeen AA Wang E Thienpont LM et 2003 CAP survey- Miller WG, Myers GL, Ashwood ER, Killeen AA, Wang E, Thienpont LM, et al. Creatinine measurement: state of the art in accuracy and inter-laboratory harmonization. Arch Pathol Lab Med 2005;129:

36 Clinical Laboratory Based Analytical Systems for Measuring Serum Creatinine to Assess GFR The methods most widely used to measure serum creatinine: alkaline picrate methods enzymatic or partially enzymatic assays HPLC methods Isotope-dilution mass spectrometry (IDMS) high-order reference methods have been developed for assignment of reference materials but are available in only a few highly hl specialized laboratories worldwide.

37 alkaline picrate methods The method of Jaffe The presence of interfering substances, particularly proteins, in serum can lead to the overestimation of serum creatinine by as much as 15% 25% by various Jaffe methodologic applications Interferences from glucose and acetoacetate are particularly important by measuring several hundred serum pools by gas chromatography (GC)-IDMS and the Jaffe method Results indicated that to get agreement with the enzymatic method, an offset of mg/dl was necessary

38 enzymatic methods Although the enzymatic methods have been reported to have generally fewer interferences than the Jaffe methods, there have been reports of various substances that do interfere

39 HPLC procedures HPLC appears to provide an excellent designated comparison method for inhouse use by manufacturers

40 ms-based procedures GC-IDMS is considered the method of choice for establishing the true concentration of creatinine in serum because of its excellent specificity and relative SD <0.3%

41 ISO for tracebility of Lab results A unified effort is required Establishing measurement traceability is an important tool This effort must involve international cooperation among the in vitro diagnostic (IVD) manufacturers, clinical laboratories,,professional organizations,,government agencies, and EQAS/PT providers. To achieve improved accuracy of creatinine results requires that the values assigned by manufacturers to calibrators and control materials are traceable to high-order h reference measurement procedures and reference materials. The international organization for standardization (iso) has developed a written standard that details a pathway for establishing traceability of clinical laboratory measurement results

42 We are not too late if we began today In 2006, a serum matrix standard reference material (SRM) was prepared by the National Institute of Standards and Technology and submitted to the Joint Committee on Traceability in Laboratory Medicine i Use of this material, in combination with the isotopedilution mass spectrometry reference method, was intended d to assist reagent manufacturers in achieving i better consensus among methods By the end of 2009, the calibration of most clinical laboratory methods was traceable to the SRM and isotope-dilution mass spectrometry

43 THE BRITISH COLOMBIA STANDARDIZATION PROGRAM J Am Soc Nephrol 19: , doi: /ASN /ASN

44 Abstract 107 laboratories, which tested creatinine on 124 analyzers from six different manufacturers, voluntarily participated Each laboratory received a correction factor to standardize them to the isotope dilution mass spectrometry reference method The adjusted values were then used to calculate egfr using the Modification of Diet in Renal Disease (MDRD) equation The standardization program reduced the average total error in the measurement of creatinine i from 23.9 to 8.7% and the average analytical bias from 16.5 to 2.7% Implementing this program on a larger scale could reduce the rate of incorrect classification of stage 3 chronic kidney disease by 84%

45 Introduction Serum creatinine test results can vary significantly between clinical laboratories, a fact that is often not well recognized by health care professionals This variation is greater in the normal and near-normal normal range of creatinine measurements Regional initiatives to implement egfr reporting must first take steps to standardize the Cr

46 Location of study British Columbia introduced egfr reporting in October 2003, and in March 2004, a provincial program was introduced to standardize the measurement of creatinine British Columbia is a province in Canada with a population of approximately 4.1 million people. The provincial creatinine standardization program is a voluntary project, which was carried out in partnership with the Canadian External Quality Assessment Laboratory

47 Results funded centrally and operates on a voluntary basis The majority (94%) of clinical ca laboratories ato in British Columbia are participating

48 %TE for the measurement of creatinine (98.9 μmol/l) at baseline. %TE for the measurement of creatinine (98.9 μmol/l) at baseline. The between-day precision (coefficient of variance) is also plotted (black bars) Komenda P et al. JASN 2008;19: by American Society of Nephrology

49 The percentage total error (%TE) ranged from 4 to 54% with an overall provincial i average of 23.9% if a serum sample with a true creatinine concentration of 100 μmol/l were to be measured in the best laboratory in the province, then the reported result would fall between 96 and 104 μmol/l 95% of the time; if it were tested in the worst lb laboratory, then the reported result would be fall between 45 and 154 μmol/l 95% of the time

laboratories in the province as compared

50 (A) Unadjusted creatinine performed on one test sample from each of the 107 laboratories in the province as compared with the reference sample. The average calibration bias for the measurement of creatinine across the province was 16.5% (positive) Komenda P et al. JASN 2008;19: by American Society of Nephrology

53 Program Cost During year 1 of the program, the first and second components and one monitoring cycle of the third component were conducted The cost of this launch phase was $335,000 This fee covered the costs associated with acquisition of the sample sets for the program, screening of these samples for viral pathogens, shipping of samples to Belgium for assignment of target values by IDMS, shipping of the samples to participating laboratories on dry ice, data acquisition, and performance reporting together with telephone and follow-up plus ongoing administrative costs The third component of the program, composed of the ongoing monitoring and auditing of the participating laboratories three times per year, costs $135,000 per year

54 This finding indicates that, in real terms, a %TE performance goal of 11.4% is certainly achievable once the manufacturers have revised their calibration processes to be traceable to the IDMS reference method

55 The results of results An estimated 145,000 people in british columbia are at increased risk for CKD If all of the adults in british iihcolumbia were to be tested using this analytical l system, then 535,000 adult british columbians (15 yr and older) would be added to an at-risk category for stage 3 renal disease when in fact they should not be Implementing this program would reduce the rate of false-positive results by 84% and keep 449,400 people from being incorrectly classified as being at risk Misclassified patients would require some form of follow-up to confirm the presence or absence of renal disease. Follow-up might consist of two office visits ($53.06) together with the a routine urinalysis ($4.98) and urinary microalbumin ($22.10) for a follow-up expenditure per patient of $80.14 Given this example, the potential savings to be realized from reducing the creatinine calibration bias from 16.5 to 2.7% would amount to $36 million. On the basis of this follow-up, the creatinine standardization program would pay for itself if it could reduce the rate of false-positive results by 0.3%.

56 RECOMMENDATIONS FOR FUTURE NEXT ACTION PLAN

Standardization of. S.M.Boutorabi DCLS,PhD

Standardization of. S.M.Boutorabi DCLS,PhD Standardization of Creatinine Assay S.M.Boutorabi DCLS,PhD Chronic kidney disease (CKD) is a major public health problem in developed countries Why measure serum creatinine? Jaffe Reaction Creatinine +picric