Radiometer Medical ApS, Åkandevej 21, DK-2700 Brønshøj, Tel: +45 38 27 38 27, radiometer

1. Physiology and clinical application RTC, October 2006 Radiometer Medical ApS, Åkandevej 21, DK-2700 Brønshøj, Tel: +45 38 27 38 27, www.radiometer.com

2. Agenda • Current clinical state for Radiometer • What is creatinine? • The kidneys • Assessment of kidney function • Creatinine in the hospital • Future clinical state for Radiometer • Read more

3. Electrolytes Metabolites Full oximetry Blood gas ICU ER PICU OR NICU LAB Current clinical state of ABL

4. Electrolytes Metabolites Full oximetry Blood gas Creatinine Our customers want more....

5. Agenda • Current clinical state for Radiometer • What is creatinine? • Metabolism • Levels of creatinine • The kidneys • Assessment of kidney function • Creatinine in the hospital • Future clinical state for Radiometer • Read more

6. Creatinine is .. • A product of normal muscle metabolism • Produced from creatine in the muscles • Serves no metabolic purpose – a waste component • Removed from the blood by the kidneys • Diagnostic value: kidney functionality

7. Levels of creatinine • Relatively constant within each individual • Due to turnover of skeletal muscle it is higher in weightlifters, lower in children and adults, especially elderly • Changes in dietary intake causes only minor fluctuations • Creatinine tends to decrease with age • Conflicting information about levels in neonates • African-American race higher muscle mass, higher Crea levels • NB! The levels are highly method specific

8. Normal range of creatinine

9. Agenda • Current clinical state for Radiometer • What is creatinine? • The kidneys • Anatomy and function • Pathology of kidneys • Assessment of kidney function • Creatinine in the hospital • Future clinical state for Radiometer • Read more

10. The kidneys • Two kidneys • Essentially a sophisticated blood filter • 180 L blood are filtered daily and 1-1,5 L of urine is formed • Important excretory and metabolic functions • Excretion of waste products, e.g. Crea • Regulation of fluid • Regulation of electrolytes • Regulation of acid-base balance • Etc

11. Anatomy of kidneys

12. Functionality of kidneys

13. Pathology of kidneys • Most kidney diseases affect the nephrons • Acute, as a result of critical illness, injury or poisoning • Chronic, as a result of slow destruction by diabetes and/or high blood pressure • Loss of filtering capacity • Impaired kidneys fail to separate albumin from the urine • Symptoms include protein, blood, glucose in the urine • Decreased kidney function • 50 % of normal: possible to live a normal life • Less than 25 %: Serious health problems • Less than 15 %: Need dialysis or transplantation to survive Blood and urine flow pattern

14. Filtration system pathology • Pre-renal • Low blood volume being presented to the glomerulus for filtration. • Causes: hypovolemia due to shock, hemorrhage, burns, salt and water depletion. • Renal: • Damage of filter • Causes: inflammatory damage • Post-renal: • Blockage on distal side of the glomerulus opposing filtration pressure. • Causes: any cause of urine retention e.g. stone in the ureter, tumor growth (prostatic carcinoma)

15. Agenda • Current clinical state for Radiometer • What is creatinine? • The Kidneys • Assessment of kidney function • Creatinine, urea, blood gases, electrolytes • Glomerular filtration rate, GFR • Standardization of Crea and GFR • Creatinine in the hospital • Future clinical state for Radiometer • Read more

16. Assessment of kidney function • Glomerular Filtration Rate - GFR - is the best estimate of kidney function • Requires creatinine measurement • Creatinine is the most important marker of kidney damage – but not the only one • Relation to urea/BUN important for more in depth diagnosis • Calculation of GFR • Urea/Crea ratio reported to give higher specificity in diagnosis • Often no strict critical values for therapy • Na and K are often included to provide a full picture of the patient status • Crea with full blood gas picture relevant for ICU patients • Risk of MOF, multi organ failure

17. Glomerular Filtration Rate - GFR • GFR calculation is more accurate for determining whether a person has reduced kidney function • Calculation of the efficiency with which the kidneys filter waste from the blood • Traditionally: Measurement of excretion and plasma level of a substance that is freely filtered by the kidneys • New equation allows for calculation from cCrea and age • Promoted by NKDEP, National Kidney Disease Education Program (USA) • Implemented on ABL8x7 FLEX GFR = k1(cCrea)k2(Age)k2 (0.741 if female) (1.210 if African-American)

18. The kidneys and GFR • Inverse proportionality between cCrea and GFR • A high GFR reflects a high filtration rate and therefore a low cCrea • Different GFRs exist • Renewed focus on GFR

19. Agenda • Current clinical state for Radiometer • What is creatinine? • The kidneys • Assessment of kidney function • Creatinine in the hospital • Where, why, when, STAT and together with what? • Acute renal failure • Chronic renal failure • Future clinical state for Radiometer • Read more

20. Current state – who wants creatinine? • Creatinine is a marker of kidney function • Patient groups found at both critical and general wards

21. Creatinine – Where, when, STAT and with what?

22. At the Hospital – Acute • Acute renal failure - ARF • Many patients in the ICU develop ARF (20-50%) • Very often surgery or shock patients • It is “sudden” - develops over 1-3 days • Characterized by • Rapid increase of both creatinine and urea, with creatinine as the most important marker • Also changes in other parameters e.g. electrolytes parameters • Therapy • Dialysis • Outcome • Some are reversible • ARF mortality rate is 40-60 %

23. At the Hospital – Chronic • Chronic kidney disease - CKD • Progressive and irreversible destruction of kidney tissue • May develop over several years • Cornerstone in diagnosis: GFR • Therapy • Change in diet • Special care for diabetics etc • Dialysis • Focus area of NKDEP

24. Treatment of renal patients • Dialysis or kidney transplantation • Life saving therapy for people with acute or chronic kidney failure • Dialysis is a method of removing toxic substances (impurities or wastes) from the blood when the kidneys are unable to do so • Each treatment has advantages and disadvantages • The patient needs to make some changes in his life, including cutting down on calories and salt in the diet

25. Treatment – kidney transplantation • Kidney transplantation surgically places a healthy kidney from another person into the patient’s body • The artery and vein of the new kidney is connected to the patient’s artery and vein so the blood flows through the donated kidney • The new kidney may start working right away or may take up to a few weeks to make urine • Unless the “old” kidneys are causing infection or high blood pressure, they are left in place

26. Treatment - hemodialysis • Blood is diverted from the venous access via dialysis catheters to a dialysis machine • Filtration through special filters along with toxin-removing solutions (dialysate) • The chemical imbalances and impurities of the blood are corrected and the blood is returned to the body • Most patients undergo hemodialysis for three sessions of three to four hours every week

27. Electrolytes Full oximetry Metabolites Blood gas Creatinine Two challenges for us • The lack of urea/BUN • Will be added to the ABL later • Some do not perceive creatinine as s STAT parameter • Is true for the majority of the creatinine measurements in the hospital • Some are STAT – therefore requested by some customers • Very strong synergy to the other ABL parameters

28. Future state - creatinine • Creatinine on a BG analyzer makes perfect sense • Increased therapeutic value of each measurement • Evaluated together with the other parameters on the BG analyzer, including the recommended GFR • Critically ill patients carry a high risk of acute renal failure

29. Read more • http://www.kidneyatlas.org/ • http://nkdep.nih.gov/labprofessionals/index.htm • http://dspace.dial.pipex.com/town/plaza/jc75/inf_2.htm • http://classes.kumc.edu/son/nurs320/module5.htm • http://www.nlm.nih.gov/medlineplus/ency/article/000501.htm#visualContent • Lawson N, Lang T, Broughton A, Prinsloo P, Turner C, Marenah C. Creatinine assays: time for action? Ann Clin Biochem 39, 599-602. 1-1-2002. • Miller W, Myers G, Ashwood E, Killeen A, Wang E, Thienpont L, et al. Creatinine measurement: state of the art in accuracy and interlaboratory harmonization. Arch Pathol Lab Med 2005; 129 (3): 297-04. • Myers GL, Miller WG, Coresh J et al. Recommendations for improving serum creatinine measurement: a report from the laboratory working group of the national kidney disease education program. Clin Chem 2005; 52, 1: 5-18. • Rowe D, Omar H, Barratt S, Biggs P. An evaluation of blood creatinine measurement by creatinase on the NOVA M7 blood gas analyzer. Clinica Chimica Acta 307, 23-26. 1-5-2001. • Papadea C, Foster J, Grant S, Ballard S, Cate J, Southgate W, et al. Evaluation of the i-STAT Portable Clinical Analyzer for point-of-care blood testing in the intensive care units of a university children's hospital. Ann Clin Lab Sci 2002;32(3):231-43.

30. RTC, October 2006 Radiometer Medical ApS, Åkandevej 21, DK-2700 Brønshøj, Tel: +45 38 27 38 27, www.radiometer.com