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CLINICAL CHEMISTRY
NON - PROTEIN NITROGEN1
OPTOM FASLU MUHAMMED
INTRODUCTION
 NPN ( Non - Protein Nitrogen ) is a “funky” term that can be
used for a bunch of different substances that have the
element nitrogen in them, but are not proteins.
 This is a little unusual, because most of the body’s nitrogen is
associated with proteins.
 There are many different unrelated NPNs, but we are only
interested in 4 of them:
 Creatinine , Blood Urea Nitrogen ( BUN ) , Uric Acid and
Ammonia
 In general, plasma NPNs are increased in renal failure and
are commonly ordered as blood tests to check renal function
2
KEY TERMS
3
 Allantoin
 Ammonia
 Azotemia
 BUN / Creat Ratio
 Creatinine Clearance
 Creatine
 Creatinine
 GFR
 Glomerulus
 Gout
 Hyper ( hypo ) uricemia
 NPN
 Pre-renal
 Post- renal
 Purines
 Renal absorption
 Renal secretion
 Uric acid
 Urea
 Uremic syndrome
 Reyes Syndrome
OBJECTIVES
 List the origin and principle clinical significance of BUN,
Creatinine, Uric Acid and Ammonia
 List the reference ranges for the 4 principle NPNs
 Discuss why creatinine is the most useful NPN to evaluate
renal function
 Calculate Creatinine Clearance
 Discuss the common methodologies used to measure BUN,
Creatinine, Uric Acid and Ammonia
4
 General ideas about the NPNs
 Antiquated term when protein – free filtrates were required
for testing
 The NPNs were used for evaluating renal function
 The NPNs include about 15 different substances
 Most NPNs are derived from protein or nucleic acid
catabolism
 Most important NPNs
 BUN ( Blood Urea Nitrogen )
 Creatinine
 Uric acid
 Ammonia
5
 BUN ( Blood Urea Nitrogen )BUN ( Blood Urea Nitrogen )
 Blood Urea Nitrogen = BUNBUN = Urea
 50% of the NPNs
 Product of protein catabolism which produces ammonia
 Ammonia is very toxic – converted to urea by the liver
 Liver converts ammonia and CO2
 Filtered by the glomerulus but also reabsorbed by renal tubules
( 40 % )
 Some is lost through the skin and the GI tract ( < 10 % )
 Plasma BUN is affected by
 Renal function
 Dietary protein
 Protein catabolism
6
Urea
 BUN disease correlationsBUN disease correlations
 Azotemia = Elevated plasma BUN
 PrerenalPrerenal ↑↑ BUNBUN ( Not related to renal function )
 Low Blood Pressure ( CHF, Shock, hemorrhage, dehydration
)
 Decreased blood flow to kidney = No filtration
 Increased dietary protein or protein catabolism
 PrerenalPrerenal ↓↓ BUNBUN ( Not related to renal function )
 Decreased dietary protein
 Increased protein synthesis ( Pregnant women , children )
7
 RenalRenal causes ofcauses of ↑↑ BUNBUN
 Renal disease with decreased glomerular filtration
 Glomerular nephritis
 Renal failure form Diabetes Mellitus
 Post renalPost renal causes ofcauses of ↑↑ BUN ( not related to renalBUN ( not related to renal
function )function )
 Obstruction of urine flow
 Kidney stones
 Bladder or prostate tumors
 UTIs
8
 BUN / Creatinine RatioBUN / Creatinine Ratio
 Normal BUN / Creatinine ratio is 10 – 20Normal BUN / Creatinine ratio is 10 – 20
to 1to 1
 Creatinine is another NPNCreatinine is another NPN
 Pre-renal increased BUN / Creat ratio
 BUN is more susceptible to non-renal
factors
 Post-renalPost-renal increased ratio BUN / Creat
ratio
 Both BUN and Creat are elevated
 RenalRenal decreased BUN / Creat ratio
 Low dietary protein or severe liver disease
Increased BUN
Normal Creat
Increased BUN
Increased Creat
9
Decreased BUN
Normal Creat
 BUN analytical methodsBUN analytical methods
 BUN is an old term, but still in common useBUN is an old term, but still in common use
 Specimen : Plasma or serum
 To convert BUN to Urea : BUN x 2.14 = Urea ( mg /
dl )
10
UREA 2 NH4
+
+ HCO3
-
Urease
NH4
+
+ 2-OXOGLUTARATE
GLDH
GLUTAMATE
NADH NAD
Measure the rate of decreased absorbance at 340 nm
NADH absorbs … NAD does not absorb
Reference range : 10 – 20 mg / dl
 CREATININE
11
Liver Amino Acids Creatine
Muscles Creatine Phosphocreatine
Muscles Phosphocreatine Creatinine
Creatinine formed at a constant rate by the muscles as a function of muscle mass
Creatinine is removed from the plasma by glomerular filtration
Creatinine is not secreted or absorbed by the renal tubules
Therefore : Plasma creatinine is a function of glomerular filtration
Unaffected by other factors
It’s a very good test to evaluate renal function
 Creatinine disease correlations
 Increased plasma creatinine associated with decreased
glomerular filtration ( renal function )
 Glomerular filtration may be 50 % of normal before
plasma creatinine is elevated
 Plasma creatinine is unaffected by diet
 Plasma creatinine is the most common test used to
evaluate renal function
 Plasma creatinine concentrations are very stable from
day to day - If there is a delta check , its very suspicious
and must be investigated
12
 Creatinine analytical techniques
 Jaffee Method ( the Classic technique )
13
Creatinine + Picrate Acid Colored chromogen
Specimen : Plasma or serum
Elevated bilirubin and hemolysis causes falsely decreased results
Reference range : 0.5 - 1.5 mg / dl
14
 URIC ACID
 Breakdown product of purines ( nucleic acid / DNA )
 Purines from cellular breakdown are converted to uric acid
by the liver
 Uric acid is filtered by the glomerulus ( but 98 – 100 %
reabsorbed )
 Elevated plasma uric acid can promote formation of solid
uric acid crystals in joints and urine
Uric acid diseases
 Gout
 Increased plasma uric acid
 Painful uric acid crystals in joints
 Usually in older males ( > 30 years-old )
 Associated with alcohol consumption
 Uric acid may also form kidney stones
 Other causes of increased uric acid
 Leukemias and lymphomas ( ↑ DNA catabolism )
 Megaloblastic anemias ( ↑ DNA catabolism )
 Renal disease ( but not very specific )
15
 Uric acid analysis
16
Uric acid + O2 + H2O Allantoin + CO2
Uricase
Uric acid absorbs light @ 293 nm , Allantoin does not.
The rate of decreased absorption is proportional to the uric acid
concentration.
Specimen : Plasma or serum
+ H2O2
Reference range : 3.5 - 7.2 mg/dl (males)
2.6 - 6.0 mg/dl (females)
Let’s remember 3.0 - 7.0 mg/dl
 AMMONIA
 Produced from the deamaination of amino acids in the
muscle and from bacteria in the GI tract
 Ammonia is very toxic - The liver converts ammonia into
urea
 Urea is less toxic and can be removed from the plasma by
the kidneys
 In severe hepatic disease, the liver fails to convert
ammonia into urea, resulting in increased plasma
ammonia levels
 Increased plasma ammonia concentrations in :
 Liver failure
 Reye’s Disease
17
18
Ammonia analytical techniques
NH4
+
+ 2-OXOGLUTARATE + NADPH L-GLUTAMATE +
NADP+
There is a decreasing absorbance @ 340 nm, proportional to the
ammonia concentration.
Specimen : EDTA or Heparinized Whole Blood on ice
Must be tested ASAP or plasma frozen
Delayed testing caused false increased values
Reference range : 20 – 60 µg / dl
 Creatinine Clearance
 Calculated measurement of the rate at which creatinine is
removed from the plasma by the kidneys
 Measurement of glomerular filtration ( renal function )Measurement of glomerular filtration ( renal function )
 A good test of glomerular filtration because
 Creatinine is an endogenous substance ( not affected by
diet )
 Creatinine is filtered by the glomerulus, but not
secreted or re-absorbed by the renal tubules
19
20
24 Hour Urine collection
Container.
The volume can be measured
directly off the container.
 Creatinine Clearance specimens
 24 hour urine specimen
 Plasma / serum creatinine collected during the urine
collection
 24 Hour Creatinine Clearance Formula
 CREATININE CLEARANCE =
21












A
U 73.1
P
V
U = Creatinine concentration of the 24 hour urine ( mg / dl )
V = 24 hour urine volume ( mls ) per minute - V / 1440 = mls / minuteper minute - V / 1440 = mls / minute
P = Plasma creatinine concentration ( mg / dl )
A = Correction factor accounts for differences in body surface area
obtained from a height – weight chart
22
Example of a 24 Hour Creatinine Clearance calculation
24 hour urine volume = 1000 mls
24 hour urine creatinine = 20.0 mg / dl
Plasma creatinine = 5.0 mg / dl
Patients height / weight = 6’00 / 190 lbs ( see pg. 680 )
( )
( )
( ) ( )
( )
100020.01.73 1.731440
5.0 2.05
UV
Creat Cl
P A
   
= = = ÷  ÷
   
Creat Cl = 2 ml / min …. Very poor clearance !!!
 Procedure for 24 Hour Urine Collection
 Have the patient empty his / her bladder ( discard this urine ).
 Note the time . For the next 24 hours, have the patient collect
and save all urine in an appropriate container.
 At the end of the 24 hour period have the patient void one last
time into the urine container. This completes the collection.
 If possible, keep the urine specimen refrigerated.
23
 Reference range
 97 - 137 ml / min ( male)
 88 - 128 ml / min (female)
 Let’s remember 90 - 130 ml / min
24
NPN TOP 10
 Increased Creatinine associated with renal failure
 Increased BUN associated with renal failure and protein catabolism
 Increased Uric Acid associated with Gout
 Increased Ammonia is associated with liver disease
 Creatinine derived from cellular creatine … very constant from day
to day
 Delta checks on plasma Creatinine must be investigated !!!
 BUN ( Urea ) is derived from protein catabolism
 Protein Ammonia Urea
 Uric Acid is derived from purine( a component of DNA ) catabolism
 Decreased Creatinine Clearance associated with decreased
Glomerular Filtration
25












=
AP
UV 73.1
ClearanceCreatinine
Don’t forget to divide V by 1440 !
REFERENCE RANGES
 BUN 10 - 20 mg / dl
 Creatinine 0.5 - 1.5 mg /dl
 Uric Acid 3.0 - 7.0 mg / dl
 Creatinine Clearance 90 - 130 ml / min
 Ammonia 20 - 60 ug / dl
 BUN / Creat Ratio 10 - 20 to 1
26

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Creatine

  • 1. CLINICAL CHEMISTRY NON - PROTEIN NITROGEN1 OPTOM FASLU MUHAMMED
  • 2. INTRODUCTION  NPN ( Non - Protein Nitrogen ) is a “funky” term that can be used for a bunch of different substances that have the element nitrogen in them, but are not proteins.  This is a little unusual, because most of the body’s nitrogen is associated with proteins.  There are many different unrelated NPNs, but we are only interested in 4 of them:  Creatinine , Blood Urea Nitrogen ( BUN ) , Uric Acid and Ammonia  In general, plasma NPNs are increased in renal failure and are commonly ordered as blood tests to check renal function 2
  • 3. KEY TERMS 3  Allantoin  Ammonia  Azotemia  BUN / Creat Ratio  Creatinine Clearance  Creatine  Creatinine  GFR  Glomerulus  Gout  Hyper ( hypo ) uricemia  NPN  Pre-renal  Post- renal  Purines  Renal absorption  Renal secretion  Uric acid  Urea  Uremic syndrome  Reyes Syndrome
  • 4. OBJECTIVES  List the origin and principle clinical significance of BUN, Creatinine, Uric Acid and Ammonia  List the reference ranges for the 4 principle NPNs  Discuss why creatinine is the most useful NPN to evaluate renal function  Calculate Creatinine Clearance  Discuss the common methodologies used to measure BUN, Creatinine, Uric Acid and Ammonia 4
  • 5.  General ideas about the NPNs  Antiquated term when protein – free filtrates were required for testing  The NPNs were used for evaluating renal function  The NPNs include about 15 different substances  Most NPNs are derived from protein or nucleic acid catabolism  Most important NPNs  BUN ( Blood Urea Nitrogen )  Creatinine  Uric acid  Ammonia 5
  • 6.  BUN ( Blood Urea Nitrogen )BUN ( Blood Urea Nitrogen )  Blood Urea Nitrogen = BUNBUN = Urea  50% of the NPNs  Product of protein catabolism which produces ammonia  Ammonia is very toxic – converted to urea by the liver  Liver converts ammonia and CO2  Filtered by the glomerulus but also reabsorbed by renal tubules ( 40 % )  Some is lost through the skin and the GI tract ( < 10 % )  Plasma BUN is affected by  Renal function  Dietary protein  Protein catabolism 6 Urea
  • 7.  BUN disease correlationsBUN disease correlations  Azotemia = Elevated plasma BUN  PrerenalPrerenal ↑↑ BUNBUN ( Not related to renal function )  Low Blood Pressure ( CHF, Shock, hemorrhage, dehydration )  Decreased blood flow to kidney = No filtration  Increased dietary protein or protein catabolism  PrerenalPrerenal ↓↓ BUNBUN ( Not related to renal function )  Decreased dietary protein  Increased protein synthesis ( Pregnant women , children ) 7
  • 8.  RenalRenal causes ofcauses of ↑↑ BUNBUN  Renal disease with decreased glomerular filtration  Glomerular nephritis  Renal failure form Diabetes Mellitus  Post renalPost renal causes ofcauses of ↑↑ BUN ( not related to renalBUN ( not related to renal function )function )  Obstruction of urine flow  Kidney stones  Bladder or prostate tumors  UTIs 8
  • 9.  BUN / Creatinine RatioBUN / Creatinine Ratio  Normal BUN / Creatinine ratio is 10 – 20Normal BUN / Creatinine ratio is 10 – 20 to 1to 1  Creatinine is another NPNCreatinine is another NPN  Pre-renal increased BUN / Creat ratio  BUN is more susceptible to non-renal factors  Post-renalPost-renal increased ratio BUN / Creat ratio  Both BUN and Creat are elevated  RenalRenal decreased BUN / Creat ratio  Low dietary protein or severe liver disease Increased BUN Normal Creat Increased BUN Increased Creat 9 Decreased BUN Normal Creat
  • 10.  BUN analytical methodsBUN analytical methods  BUN is an old term, but still in common useBUN is an old term, but still in common use  Specimen : Plasma or serum  To convert BUN to Urea : BUN x 2.14 = Urea ( mg / dl ) 10 UREA 2 NH4 + + HCO3 - Urease NH4 + + 2-OXOGLUTARATE GLDH GLUTAMATE NADH NAD Measure the rate of decreased absorbance at 340 nm NADH absorbs … NAD does not absorb Reference range : 10 – 20 mg / dl
  • 11.  CREATININE 11 Liver Amino Acids Creatine Muscles Creatine Phosphocreatine Muscles Phosphocreatine Creatinine Creatinine formed at a constant rate by the muscles as a function of muscle mass Creatinine is removed from the plasma by glomerular filtration Creatinine is not secreted or absorbed by the renal tubules Therefore : Plasma creatinine is a function of glomerular filtration Unaffected by other factors It’s a very good test to evaluate renal function
  • 12.  Creatinine disease correlations  Increased plasma creatinine associated with decreased glomerular filtration ( renal function )  Glomerular filtration may be 50 % of normal before plasma creatinine is elevated  Plasma creatinine is unaffected by diet  Plasma creatinine is the most common test used to evaluate renal function  Plasma creatinine concentrations are very stable from day to day - If there is a delta check , its very suspicious and must be investigated 12
  • 13.  Creatinine analytical techniques  Jaffee Method ( the Classic technique ) 13 Creatinine + Picrate Acid Colored chromogen Specimen : Plasma or serum Elevated bilirubin and hemolysis causes falsely decreased results Reference range : 0.5 - 1.5 mg / dl
  • 14. 14  URIC ACID  Breakdown product of purines ( nucleic acid / DNA )  Purines from cellular breakdown are converted to uric acid by the liver  Uric acid is filtered by the glomerulus ( but 98 – 100 % reabsorbed )  Elevated plasma uric acid can promote formation of solid uric acid crystals in joints and urine
  • 15. Uric acid diseases  Gout  Increased plasma uric acid  Painful uric acid crystals in joints  Usually in older males ( > 30 years-old )  Associated with alcohol consumption  Uric acid may also form kidney stones  Other causes of increased uric acid  Leukemias and lymphomas ( ↑ DNA catabolism )  Megaloblastic anemias ( ↑ DNA catabolism )  Renal disease ( but not very specific ) 15
  • 16.  Uric acid analysis 16 Uric acid + O2 + H2O Allantoin + CO2 Uricase Uric acid absorbs light @ 293 nm , Allantoin does not. The rate of decreased absorption is proportional to the uric acid concentration. Specimen : Plasma or serum + H2O2 Reference range : 3.5 - 7.2 mg/dl (males) 2.6 - 6.0 mg/dl (females) Let’s remember 3.0 - 7.0 mg/dl
  • 17.  AMMONIA  Produced from the deamaination of amino acids in the muscle and from bacteria in the GI tract  Ammonia is very toxic - The liver converts ammonia into urea  Urea is less toxic and can be removed from the plasma by the kidneys  In severe hepatic disease, the liver fails to convert ammonia into urea, resulting in increased plasma ammonia levels  Increased plasma ammonia concentrations in :  Liver failure  Reye’s Disease 17
  • 18. 18 Ammonia analytical techniques NH4 + + 2-OXOGLUTARATE + NADPH L-GLUTAMATE + NADP+ There is a decreasing absorbance @ 340 nm, proportional to the ammonia concentration. Specimen : EDTA or Heparinized Whole Blood on ice Must be tested ASAP or plasma frozen Delayed testing caused false increased values Reference range : 20 – 60 µg / dl
  • 19.  Creatinine Clearance  Calculated measurement of the rate at which creatinine is removed from the plasma by the kidneys  Measurement of glomerular filtration ( renal function )Measurement of glomerular filtration ( renal function )  A good test of glomerular filtration because  Creatinine is an endogenous substance ( not affected by diet )  Creatinine is filtered by the glomerulus, but not secreted or re-absorbed by the renal tubules 19
  • 20. 20 24 Hour Urine collection Container. The volume can be measured directly off the container.
  • 21.  Creatinine Clearance specimens  24 hour urine specimen  Plasma / serum creatinine collected during the urine collection  24 Hour Creatinine Clearance Formula  CREATININE CLEARANCE = 21             A U 73.1 P V U = Creatinine concentration of the 24 hour urine ( mg / dl ) V = 24 hour urine volume ( mls ) per minute - V / 1440 = mls / minuteper minute - V / 1440 = mls / minute P = Plasma creatinine concentration ( mg / dl ) A = Correction factor accounts for differences in body surface area obtained from a height – weight chart
  • 22. 22 Example of a 24 Hour Creatinine Clearance calculation 24 hour urine volume = 1000 mls 24 hour urine creatinine = 20.0 mg / dl Plasma creatinine = 5.0 mg / dl Patients height / weight = 6’00 / 190 lbs ( see pg. 680 ) ( ) ( ) ( ) ( ) ( ) 100020.01.73 1.731440 5.0 2.05 UV Creat Cl P A     = = = ÷  ÷     Creat Cl = 2 ml / min …. Very poor clearance !!!
  • 23.  Procedure for 24 Hour Urine Collection  Have the patient empty his / her bladder ( discard this urine ).  Note the time . For the next 24 hours, have the patient collect and save all urine in an appropriate container.  At the end of the 24 hour period have the patient void one last time into the urine container. This completes the collection.  If possible, keep the urine specimen refrigerated. 23
  • 24.  Reference range  97 - 137 ml / min ( male)  88 - 128 ml / min (female)  Let’s remember 90 - 130 ml / min 24
  • 25. NPN TOP 10  Increased Creatinine associated with renal failure  Increased BUN associated with renal failure and protein catabolism  Increased Uric Acid associated with Gout  Increased Ammonia is associated with liver disease  Creatinine derived from cellular creatine … very constant from day to day  Delta checks on plasma Creatinine must be investigated !!!  BUN ( Urea ) is derived from protein catabolism  Protein Ammonia Urea  Uric Acid is derived from purine( a component of DNA ) catabolism  Decreased Creatinine Clearance associated with decreased Glomerular Filtration 25             = AP UV 73.1 ClearanceCreatinine Don’t forget to divide V by 1440 !
  • 26. REFERENCE RANGES  BUN 10 - 20 mg / dl  Creatinine 0.5 - 1.5 mg /dl  Uric Acid 3.0 - 7.0 mg / dl  Creatinine Clearance 90 - 130 ml / min  Ammonia 20 - 60 ug / dl  BUN / Creat Ratio 10 - 20 to 1 26