1. Physiology and clinical application
Overlapping with clinical presentation from Crea conference, January 2006
Physiology and clinical application
RTC, October 2006
Radiometer Medical ApS, Åkandevej 21, DK-2700 Brønshøj, Tel: ,

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. Current clinical state of ABL
Electrolytes
Metabolites
Full oximetry
The ABL parameters provide the clinician with an overview of the patient’s clinical state. There is synergy between the parameters – they affect each other, and they describe various angles of the story.
The synergy is requested for patients in many departments of the hospital.
Blood gas ER
NICU OR
PICU
LAB
ICU

4. Our customers want more....
Electrolytes
Metabolites
Full oximetry
With the addition of Crea, additional information is provided to the clinician.
Crea has a great deal of synergy with the electrolyte values and represent a piece of the “assessing kidney function” puzzle
Blood gas
Creatinine

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
µmol/L
mg/dL
Male
80-133
Female
62-115
Neonate
0-1 week
1 week-1 month
1-6 months
53-97
27-62
18-35

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
Your kidneys are bean-shaped organs, each about the size of your fist. They are located near the middle of your back, just below the rib cage. The kidneys are sophisticated reprocessing machines. The waste and extra water become urine, which flows to your bladder through tubes called ureters. Your bladder stores urine until you go to the bathroom.
The wastes in your blood come from the normal breakdown of active tissues and from the food you eat. Your body uses the food for energy and self-repair. After your body has taken what it needs from the food, waste is sent to the blood. If your kidneys did not remove these wastes, the wastes would build up in the blood and damage your body.

12. Functionality of kidneys
The actual filtering occurs in tiny units inside your kidneys called nephrons. Every kidney has about a million nephrons. In the nephron, a glomerulus—which is a tiny blood vessel, or capillary—intertwines with a tiny urine-collecting tube called a tubule. A complicated chemical exchange takes place, as waste materials and water leave your blood and enter your urinary system.
At first, the tubules receive a combination of waste materials and chemicals that your body can still use. Your kidneys measure out chemicals like sodium, phosphorus, and potassium and release them back to the blood to return to the body. In this way, your kidneys regulate the body’s level of these substances. The right balance is necessary for life, but excess levels can be harmful.

13. Blood and urine flow pattern
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
Your health care team may talk about the work your kidneys do as renal function. If you have two healthy kidneys, you have 100 percent of your renal function. This is more renal function than you really need. Some people are born with only one kidney, and these people are able to lead normal, healthy lives. Many people donate a kidney for transplantation to a family member or friend. Small declines in renal function may not cause a problem.
But many people with reduced renal function have a kidney disease that will get worse. You will have serious health problems if you have less than 25 percent of your renal function. If your renal function drops below 10 to 15 percent, you cannot live long without some form of renal replacement therapy—either dialysis or transplantation
Diabetic Nephropathy
Diabetes is a disease that keeps the body from using glucose (sugar) as it should. If glucose stays in your blood instead of breaking down, it can act like a poison. Damage to the nephrons from unused glucose in the blood is called diabetic nephropathy. If you keep your blood glucose levels down, you can delay or prevent diabetic nephropathy.
High Blood Pressure
High blood pressure can damage the small blood vessels in your kidneys. The damaged vessels cannot filter wastes from your blood as they are supposed to.
Your doctor may prescribe blood pressure medication. Blood pressure medicines called angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been found to protect the kidneys even more than other medicines that lower blood pressure to similar levels. The National Heart, Lung, and Blood Institute (NHLBI), one of the National Institutes of Health, recommends that people with diabetes or reduced kidney function should keep their blood pressure below 130/80 mm Hg.
Glomerular Diseases
Several different types of kidney disease are grouped together under this category, including autoimmune diseases, infection-related diseases, and sclerotic diseases. As the name indicates, glomerular diseases attack the tiny blood vessels (glomeruli) within the kidney. The most common primary glomerular diseases include membranous nephropathy, IgA nephropathy, and focal segmental glomerulosclerosis. Protein, blood, or both in the urine are often the first signs of these diseases. They can slowly destroy kidney function. Blood pressure control is important with any kidney disease. Treatments for glomerular diseases may include immunosuppressive drugs or steroids to reduce inflammation and proteinuria, depending on the specific disease.
Inherited and Congenital Kidney Diseases
Some kidney diseases result from hereditary factors. Polycystic kidney disease (PKD), for example, is a genetic disorder in which many cysts grow in the kidneys. PKD cysts can slowly replace much of the mass of the kidneys, reducing kidney function and leading to kidney failure.
Microalbuminuria and Proteinuria
Healthy kidneys take wastes out of the blood but leave protein. Impaired kidneys may fail to separate a blood protein called albumin from the wastes. At first, only small amounts of albumin may leak into the urine, a condition known as microalbuminuria, a sign of deteriorating kidney function. As kidney function worsens, the amount of albumin and other proteins in the urine increases, and the condition is called proteinuria. Your doctor may test for protein using a dipstick in a small sample of your urine taken in the doctor’s office. The color of the dipstick indicates the presence or absence of proteinuria.
A more sensitive test for protein or albumin in the urine involves laboratory measurement and calculation of the protein-to-creatinine or albumin-to-creatinine ratio. This test should be used to detect kidney disease in people at high risk, especially those with diabetes. If your first laboratory test shows high levels of protein, another test should be done 1 to 2 weeks later. If the second test also shows high levels of protein, you have persistent proteinuria and should have additional tests to evaluate your kidney function.
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)
Filtration system analogue
Pre-renal: rate of which the liquid is presented to the filter
Renal: the patency of the filter (a blocked filter will result in lower filtration rate)
Post-renal: opposing pressure on the other side of the filter will tend to reduce the rate
Similar to bilirubin, where there is a pre-hepatic, a hepatic and a post-hepatic condition

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
Urea/Crea ratio: usually 12-20
Urea/Crea >20:1 with normal creatinine
Urea/Crea (>20:1) with elevated creatinine
Urea/Crea (<10:1) with decreased BUN
Urea/Crea (<10:1) with increased creatinine

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
Glomerular Filtration Rate (GFR) Based on Creatinine Measurement
GFR is a calculation of how efficiently the kidneys are filtering wastes from the blood. A traditional GFR calculation requires an injection into the bloodstream of a substance that is later measured in a 24-hour urine collection. Recently, scientists found they could calculate GFR without an injection or urine collection. The new calculation requires only a measurement of the creatinine in a blood sample.
Creatinine is a waste product in the blood created by the normal breakdown of muscle cells during activity. Healthy kidneys take creatinine out of the blood and put it into the urine to leave the body. When kidneys are not working well, creatinine builds up in the blood.
In the lab, your blood will be tested to see how many milligrams of creatinine are in one deciliter of blood (mg/dL). Creatinine levels in the blood can vary, and each laboratory has its own normal range, usually 0.6 to 1.2 mg/dL. If your creatinine level is only slightly above this range, you probably will not feel sick, but the elevation is a sign that your kidneys are not working at full strength. One formula for estimating kidney function equates a creatinine level of 1.7 mg/dL for most men and 1.4 mg/dL for most women to 50 percent of normal kidney function. But because creatinine values are so variable and can be affected by diet, a GFR calculation is more accurate for determining whether a person has reduced kidney function.
The new GFR calculation uses the patient’s creatinine measurement along with weight, age, and values assigned for sex and race. Some medical laboratories may make the GFR calculation when a creatinine value is measured and include it on their lab report.
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
New equation allows for calculation from cCrea and age
Promoted by NKDEP, National Kidney Disease Education Program (USA)

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
WHERE
WHY ER
For selected critical patients
ICU
Renal function, ARF, hydration status
NICU/PICU OR
Renal function, hydration status
Dialysis
Renal function, monitor therapy
General wards
CT scan
To control possible kidney damage
ARF – acute renal failure
CT scan – computed tomography. The kidneys are sensitive to the contrast material. Controlling Crea before and after scan

21. Creatinine – Where, when, STAT and with what?
As needed
Yes
Some always order creatinine and urea/BUN together, some don’t.
Other creatinine partners:
Na, K, Cl, HCO3-, tHb, iCa
ICU
1-2/days
Sometimes OR
Before surgery
NICU/PICU
Dialysis
1/week to
1/month No
General wards
1/day
CT scan
Before a scan
Typically only creatinine
X-ray/CT scan: contrast liquid may damage kidneys

22. At the Hospital – Acute WHERE ? ER Acute renal failure - ARF ICU
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 %
WHERE ? ER
ICU
NICU/PICU OR

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
WHERE
All departments

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
PERITONEAL DIALYSIS
Peritoneal dialysis works by using the body's peritoneal membrane, which is inside the abdomen, as a semi-permeable membrane. Special solutions that help remove toxins are infused in, remain in the abdomen for a time, and then are drained out. This form of dialysis can be performed at home, but must be done on a continuous, everyday basis.
HEMODIALYSIS
Hemodialysis works by circulating the blood through special filters. The blood flows across a semi-permeable membrane (the dialyzer or filter), along with solutions that help remove toxins. Hemodialysis requires a blood flow of 400 to 500 milliliters per minute (ml/min). A normal IV tube in an arm or leg will not support that volume of blood flow. Special forms of accessing your circulatory system are therefore required.
The access can be temporary or permanent. Temporary access takes the form of dialysis catheters. These are large-bore catheters placed in large veins that can support acceptable blood flows. Most catheters are used in emergency situations, for short periods of time. However, catheters called tunneled catheters can be used for prolonged periods of time, often weeks to months.
Permanent access is created by surgically joining an artery to a vein. This allows the vein to receive blood at high pressure, leading to thickening of the vein's wall. Now this "arterialized vein" can sustain repeated puncture and also provides excellent blood flow rates. The connection between an artery and a vein can be made using blood vessels (an arteriovenous fistula, or AVF) or a synthetic bridge (arteriovenous graft, or AVG).
The AVF is more desirable, because rates of infection are very low and it is quite durable. It may take many months for the AVF to mature, so careful planning is required.
The AVG can be accessed a few weeks after creation. It provides good flows but has a high complication rate. It should be attempted only if the AVF is not feasible.
Blood is diverted from the access to a dialysis machine. Here, the blood flows counter-current to a special solution called the dialysate. The chemical imbalances and impurities of the blood are corrected and the blood is then returned to the body. Typically, most patients undergo hemodialysis for three sessions every week. Each session lasts 3-4 hours.

27. Two challenges for us Creatinine 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
Electrolytes
Blood gas
Metabolites
Full oximetry
Creatinine

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/
Lawson N, Lang T, Broughton A, Prinsloo P, Turner C, Marenah C. Creatinine assays: time for action? Ann Clin Biochem 39,
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):
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,
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):

30. RTC, October 2006
Radiometer Medical ApS, Åkandevej 21, DK-2700 Brønshøj, Tel: ,