Clinical chemistry chapter 9
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CLINICAL CHEMISTRY CHAPTER 9. NON - PROTEIN NITROGEN. 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.

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CLINICAL CHEMISTRY CHAPTER 9

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Clinical chemistry chapter 9

CLINICAL CHEMISTRYCHAPTER 9

NON - PROTEIN NITROGEN


Introduction

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


Key terms

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

Key Terms


Objectives

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


Clinical chemistry chapter 9

  • 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


Clinical chemistry chapter 9

  • BUN ( Blood Urea Nitrogen )

    • Blood Urea Nitrogen = BUN = 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

Urea


Clinical chemistry chapter 9

  • BUN disease correlations

    • Azotemia = Elevated plasma BUN

    • Prerenal BUN( 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

    • Prerenal  BUN( Not related to renal function )

      • Decreased dietary protein

      • Increased protein synthesis ( Pregnant women , children )


Clinical chemistry chapter 9

  • Renal causes of  BUN

    • Renal disease with decreased glomerular filtration

      • Glomerular nephritis

      • Renal failure form Diabetes Mellitus

  • Post renal causes of  BUN ( not related to renal function )

    • Obstruction of urine flow

      • Kidney stones

      • Bladder or prostate tumors

      • UTIs


Clinical chemistry chapter 9

  • BUN / Creatinine Ratio

    • Normal BUN / Creatinine ratio is 10 – 20 to 1

    • Creatinine is another NPN

    • Pre-renal increased BUN / Creat ratio

    • BUN is more susceptible to non-renal factors

    • Post-renal increased ratio BUN / Creat ratio

    • Both BUN and Creat are elevated

    • Renaldecreased BUN / Creat ratio

    • Low dietary protein or severe liver disease


Clinical chemistry chapter 9

  • BUN analytical methods

    • BUN 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 )

Urease

2 NH4+ + HCO3-

UREA

GLDH

NH4+ + 2-OXOGLUTARATE

GLUTAMATE

NADH

NAD

Measure the rate of decreased absorbance at 340 nm

NADH absorbs … NAD does not absorb

Reference range : 10 – 20 mg / dl


Clinical chemistry chapter 9

Liver Amino Acids Creatine

Muscles Creatine Phosphocreatine

Muscles Phosphocreatine Creatinine

  • 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


Clinical chemistry chapter 9

  • 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


Clinical chemistry chapter 9

  • Creatinine analytical techniques

    • Jaffee Method ( the Classic technique )

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


Clinical chemistry chapter 9

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


Clinical chemistry chapter 9

  • 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 )


Clinical chemistry chapter 9

Uricase

Uric acid + O2 + H2O

Allantoin + CO2

+

H2O2

  • Uric acid analysis

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

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


Clinical chemistry chapter 9

  • 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


Clinical chemistry chapter 9

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


Clinical chemistry chapter 9

  • Creatinine Clearance

    • Calculated measurement of the rate at which creatinine is removed from the plasma by the kidneys

    • 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


Clinical chemistry chapter 9

24 Hour Urine collection

Container.

The volume can be measured

directly off the container.


Clinical chemistry chapter 9

  • Creatinine Clearance specimens

    • 24 hour urine specimen

    • Plasma / serum creatinine collected during the urine collection

    • 24 Hour Creatinine Clearance Formula

  • CREATININE CLEARANCE =

  • U = Creatinine concentration of the 24 hour urine ( mg / dl )

    V = 24 hour urine volume ( mls ) per 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


    Clinical chemistry chapter 9

    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 )

    Creat Cl = 2 ml / min …. Very poor clearance !!!


    Clinical chemistry chapter 9

    • 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 timeinto the urine container. This completes the collection.

      • If possible, keep the urine specimen refrigerated.


    Clinical chemistry chapter 9

    • Reference range

      • 97 - 137 ml / min ( male)

      • 88 - 128 ml / min (female)

      • Let’s remember 90 - 130 ml / min


    Npn top 10

    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

    Don’t forget to divide V by 1440 !


    Reference ranges

    Reference Ranges

    • BUN10 - 20 mg / dl

    • Creatinine0.5 - 1.5 mg /dl

    • Uric Acid3.0 - 7.0 mg / dl

    • Creatinine Clearance90 - 130 ml / min

    • Ammonia20 - 60ug / dl

    • BUN / Creat Ratio10 - 20 to 1


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