1. David Schaffner Ph.D., MT(ASCP) Scientific Affairs Manager Beckman Coulter, Inc. dfschaffner@BeckmanCoulter.com Chronic Kidney Disease (CKD) Clinical and Laboratory Management of a Killer

2. Learning Objectives Analyze the incidence and epidemiology of chronic kidney disease Explain renal Function and physiology Discuss the clinical management of CKD including current guidelines for monitoring and treatment Identify the role of the Clinical Laboratory in the management of CKD including creatinine standardization and eGFR Reporting

3. Chronic Kidney Disease: Clinical and Laboratory Management of a Killer A Worldwide Health Issue: Incidence and Epidemiology Review of Renal Function and Physiology Clinical Management of CKD –Definition and Staging (K/DOQI and NKDEP) –Risk Factors –Complications and Comorbidities –NKDEP and NKF Recommendations for Monitoring and Treatment Laboratory Management of CKD –Creatinine Standardization –eGFR Reporting What Beckman Coulter is Doing Summary and Conclusions For More Information

4. A Worldwide Health Issue: ESRD Rates Continue to Rise in the US

5. Kidney Failure Deaths Compared to Cancer Deaths in the U.S. in 2000 (in Thousands) Lung Cancer Kidney Failure Colorectal Cancer Breast Cancer Prostate Cancer 57 100 41 30 160

6. Prevalence of Renal Insufficiency in U.S. GFR (mL/min/1.73 m 2 ) 59-3029-15 Number of People7.7 Million360,000 Thus, about 8 million Americans have a GFR less than 60 mL/min/1.73 m 2. Plus 11 million more have a GFR over 60 but have persistent microalbuminuria.

7. Incident Counts & Adjusted Rates, By Primary Diagnosis USRDS, 2004

8. Incidence of Kidney Failure (per million population, 1990, from HSA) USRDS, 2000

9. Incidence of Kidney Failure (per million population, 2000, by HSA)

10. Costs of Kidney Failure are High (in $billions for 2002) Kidney Failure Care Total NIH Budget 25.2 23.2 Kidney Failure Accounts for 6% of Medicare Payments Lost Income for Patients is $2-4 Billion/Yr

11. A Worldwide Health Issue Worldwide, 1.1 to 1.8 Million people have ESRD today, and is increasing 7% per year China, Australia, and other countries report similar CKD prevalence as the US at 11% Diabetes, a major cause of CKD, is increasing worldwide

12. Four (4) Major Functions: –Excretion of protein metabolism end-products –Regulation of fluid, electrolyte and acid-base balance –Hormonal Functions –Formation of Urine Review of Renal Function and Physiology

14. 25% of cardiac output goes to the kidneys The glomerulus filters up to 130mL/minute = 180L/Day –This glomerular filtration rate (GFR) is a key indicator of kidney function Tubules conserve important metabolites and reduce the filtration volume to ~ 1.5 L urine /day Normal glomeruli do not pass proteins. The more extensive the kidney damage, more protein and larger proteins will pass through. Review of Renal Function and Physiology

15. CKD: Definition and Staging per National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (K/DOQI) Definition of Chronic Kidney Disease is: –Kidney Damage lasting >3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, and manifested by either: Pathological Abnormalities, or Markers of kidney damage, including abnormalities in the composition of blood or urine, or abnormalities in imaging tests OR –GFR 3 months, with or without kidney damage

16. CKD: Definition and Staging per National Kidney Disease Education Program (NKDEP) Definition of Chronic Kidney Disease is: –The persistent and usually progressive reduction in glomerular filtration rate (GFR less than 60 mL/min/ 1/73 m 2 ) And/Or –Albuminuria (more than 30 mg of urinary albumin per gram of urine creatinine)

17. CKD: Definition and Staging per National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (K/DOQI) Stages of CKD are:

18. Risk Factors Contributing to CKD (per K/DOQI) Susceptibility Factors –Age –Race –Socioeconomic Factors –Genetic Factors / Family History Initiation Factors –Diabetes –Hypertension –Autoimmune Diseases –Urinary infections and stones

19. The Risk of Kidney Failure is Not Uniform Relative risks compared to Whites: African Americans3.8 X Native Americans2.0 X Asians/Pacific Islander1.3 X The relative risk of Hispanics compared to non-Hispanics is about 1.5 X USRDS, 2004

20. Complications of CKD Cardiovascular Disease (CVD) Anemia of Renal Failure Bone Disease Others

21. CKD and CVD CKD Patients are in the highest risk group for cardiovascular disease Cardiovascular events are the major cause of morbidity and mortality in CKD patients Early intervention and aggressive treatment is essential –Manage traditional CVD risk factors hypertension, cholesterol, smoking, exercise, weight, etc. –Manage specific CKD risk factors prothrombotic factors, chronic inflammation,, oxidative stress, etc.

22. CKD Predicts CVD Go, et al., 2004 Age-Standardized Rate of Cardiovascular Events (per 100 person- yr) Estimated GFR (mL/min/1.73 m2)

23. NACB Draft LMPG on Emerging Biomarkers of Cardiovascular Disease and Stroke: Recommendation #1 on Markers of Renal Impairment and CVD Risk: –CKD Testing, including microalbuminuria and serum creatinine for GFR estimation, should be performed for all individuals with hypertension, diabetes, family history of CKD, and those with CVD or at increased risk of CVD. In addition, measurement of serum creatinine for GFR estimation should be performed for all individuals >65 years old. Individual decision making is recommended for individuals with other CKD risk factors.

24. Anemia of Renal Failure

25. CKD and Bone Disease Significant imbalances in mineral and bone metabolism occur in CKD Long-term effects of bone disease may lead to impaired pulmonary function, cardiac hypertrophy, congestive heart failure Hyperphosphatemia and hyper-PTH

26. Monitoring and Treatment (per NKDEP and NKF) –The following information on CKD testing and treatment is drawn directly from the US National Kidney Disease Education Program and from the National Kidney Foundation

27. CKD is Not Being Recognized or Treated Most practices screen fewer than 20% of their Medicare patients with diabetes Patients are referred late to a nephrologist, especially African-American men Less than 1/3 of people with identified CKD get an ACE Inhibitor

28. Early Treatment Makes a Difference Brenner, et al., 2001

29. Parallels Between Hypertension in 1972 and Kidney Disease in 2007 Recent documentation of effective therapy Treatment of a silent disease to reduce risk for a disastrous outcome Simple screening Advantages for patients care

30. Primary Care Providers Must be Engaged 1)7.7 million people with GFR 30-60 mL/min/1.73 m 2 2)About 5,000 full-time nephrologists 3)Nearly 1,500 new patients per nephrologist Therefore, 7 new patients per day per nephrologist. Obviously not possible.

31. What can Primary Care Providers do? Recognize who is at risk Provide testing and treatment Encourage labs to provide and report estimated GFR and spot urine albumin/creatinine ratios

32. Who to Test for Chronic Kidney Disease Regular testing of people at risk Diabetes Hypertension Family History with kidney failure Cardiovascular disease

33. How to Test for Chronic Kidney Disease* In individuals with diabetes: “Spot” urine albumin to creatinine ratio Serum Creatinine and eGFR In others at risk: “Spot” urine albumin to creatinine ratio OR standard dipstick (Bouleware, et al., 2003) Estimate GFR from serum creatinine using the MDRD prediction equation *24 hour urine collections are NOT needed. Diabetics should be tested once a year. Others at risk testing less frequently as long as normal.

34. Who Should be Treated for Chronic Kidney Disease With diabetes: With urine albumin/creatinine ratios more than 30mg albumin/1 gram creatinine Without diabetes: With urine albumin/creatinine ratios more than 300mg albumin/1 gram creatinine corresponding to about 1+ on standard dipstick Or Any patient: With estimated GFR less than 60 mL/min/1.73 m 2

35. Treatment to Prevent Progression of CKD to Kidney Failure Intensive glycemic control lessens progression from microalbuminuria in type 1 diabetes - DCCT, 1993 Antihypertensive therapy with ACE Inhibitors lessens proteinuria and progression - Giatras, et al., 1997 - Psait, et al., 2000 - Jafar, et al., 2001 Low protein diets lessen progression - Fouque, et al., 1992 - Pedrini, et al., 1996 - Kasiske, et al., 1998 Meta-Analyses

36. How to Treat for Chronic Kidney Disease Maintain blood pressure less than 130/80 mmHg Use an Angiotensin Converting Enzyme (ACE) Inhibitor or Angiotensin Receptor Blocker(ARB) More than one drug is usually required and a diuretic should be part of the regimen Continue best possible glycemic control in individuals with diabetes

37. How to Treat for Chronic Kidney Disease (continued) Refer to dietician for a reduced protein diet Consult a nephrologist early Team with the nephrologist for care if GFR is less than 30 mL/min/1.73 m 2 Monitor hemoglobin and phosphorous with treatment as needed Monitor and treat cardiovascular risk, especially smoking and hypercholesterolemia

38. Kidney failure is a public health problem Economical, effective testing and therapy exist Testing and therapy are inadequately applied Reasons for a National Kidney Disease Education Program (NKDEP)

39. Worldwide Creatinine Standardization Program The National Kidney Disease Education Program (NKDEP) was established under the US NIH NIDDK NKDEP in collaboration with the International Federation of Clinical Chemistry (IFCC) and the European Communities Confederation of Clinical Chemistry (EC4) has launched the Creatinine Standardization Program. Worldwide Program Goals –To reduce inter-laboratory variation in creatinine assay calibration –To provide more accurate estimates of GFR –To help health care providers better identify and treat chronic kidney disease in order to prevent or delay kidney failure and to improve patient outcomes.

40. NKDEP Lab Working Group – Recommendations for Creatinine Creatinine methods used in reporting eGFR should be standardized to Isotope Dilution Mass Spec (IDMS) Implement eGFR reporting now, using the MDRD equation and report along with Creatinine results Report eGFR above 60 as >60 mL/min/1.73 m 2 Report Serum Creatinine values to 2 decimal places for mg/dL, or to the nearest whole number for μmol/L. Report eGFR to the nearest whole number.

41. NKDEP Lab Working Group – Recommendations for Creatinine Methodologies: Jaffe vs. Enzymatic –Jaffe Methodologies Well-established, lower cost Known interferences –Enzymatic Methodologies Newer methods, higher cost Known Interferences –NKDEP/IFCC Studies being planned to compare specificities/performance of current Jaffe and Enzymatic assays

42. The MDRD Equation for eGFR There are several equations that convert creatinine values into an estimated GFR (eGFR) NKDEP recommends the MDRD Equation –From the Modification of Diet in Renal Disease clinical study –Combines Serum Creatinine results, age, gender, race –Should be implemented on the LIS

43. NKDEP states that eGFR by MDRD is more accurate than creatinine clearance measurements. NKDEP recommends that creatinine clearance not be performed except when basal creatinine production is expected to be abnormal (obese, malnourished, muscle- wasting diseases, etc) NKDEP Lab Working Group – Recommendations for Creatinine and eGFR

44. The MDRD Equation For use with conventional Creatinine results: eGFR (mL/min/1.73 m 2 ) = 186 x (serum creatinine, mg/dL) -1.154 x (Age) -0.203 x 0.742 (if Female) x 1.21 (if African-American)

45. The MDRD Equation For use with conventional IDMS-standardized Creatinine results: eGFR (mL/min/1.73 m 2 ) = 186 175 x (serum creatinine, mg/dL) -1.154 x (Age) -0.203 x 0.742 (if Female) x 1.21 (if African-American) Versions also available in SI units (umol/L)

46. Sample eGFR Reports Sample report for a 63-year-old woman Creatinine = 1.82 mg/dL (161 μmol/L) eGFR if African American = 36 mL/min/1.73 m2 eGFR if non-African American = 30 mL/min/1.73 m2 Sample report for a 63-year-old woman identified as African American Creatinine = 1.82 mg/dL (161 μmol/L) eGFR = 36 mL/min/1.73 m2 Sample report for a 62-year-old man Creatinine = 1.35 mg/dL (119 μmol/L) eGFR if African American = >60 mL/min/1.73 m2 eGFR if non-African American = 57 mL/min/1.73 m2 Sample report for a 55-year-old man Creatinine = 1.07 mg/dL (95 μmol/L) eGFR if African American = >60 mL/min/1.73 m2 eGFR if non-African American = >60 mL/min/1.73 m2

47. MDRD Limitations NKDEP notes that the MDRD equation was NOT validated for: –Children <18 years –Seniors >75 years –“Normals” or GFR >90 ml/min/1.73 m 2 –Pregnancy –Serious comorbid conditions –Extremes of body size, muscle mass, nutritional status

48. PT/EQA Implications PT/EQA providers are making changes in participant grading to account for bimodal distributions of results. NKDEP is communicating with PT/EQA providers and IVD manufacturers to ensure appropriate grading during this transition.

49. NKDEP Lab Working Group Recommendations for Communications Communicate with clinical staff before transitioning creatinine results Communicate with Pharmacy before transitioning creatinine results –Pharmacy may be estimating GFR by other equations: Cockroft-Gault, Schwartz, or Counahan-Barratt –Transitioning to IDMS Creatinine may affect their results. And their dosing.

50. What Beckman Coulter is Doing Creatinine reagents on all Beckman Coulter systems are standardized to the internationally recommended IDMS standard No reagent or calibrator reformulations necessary Software released Summer of 2007 Labs may see recovery shifts down of 0.1 – 0.2 mg/dL (9-18 μmol/L)

51. What Beckman Coulter is Doing Beckman Coulter staff serve on the NKDEP Laboratory Working Group and on its Microalbumin Standardization Committee Published 3 Customer Letters and distributed the NKDEP/IFCC/EC4 Letter Published 2 articles in Diagnostics Today Webinar presentation at: www.BeckmanCoulter.com Published Creatinine Standardization Checklist Holding Customer Symposia, Lectures, and Workshops

52. Summary and Conclusions Chronic Kidney Disease is a worldwide killer that is under-diagnosed and under- treated. Clinical Laboratorians have a critical and central role in addressing CKD: its causes, its complications, and its treatment Beckman Coulter can help you make a difference in people’s lives.

53. For More Information www.nkdep.nih.gov –www.nkdep.nih.gov/resources –www.nkdep.nih.gov/labprofessionals www.kidney.org www.kdoqi.org www.beckmancoulter.com/customersupport /trainingeducation/elearning/course.asp Clinical Chemistry 52:1; 5-18 (Jan 2006)

54. Thank you David Schaffner Ph.D., MT(ASCP) Scientific Affairs Manager Beckman Coulter, Inc. dfschaffner@BeckmanCoulter.com