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CLINICAL CHEMISTRY CHAPTER 9

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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  1. CLINICAL CHEMISTRYCHAPTER 9 NON - PROTEIN NITROGEN

  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

  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 Key Terms

  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

  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

  6. 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

  7. 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 )

  8. 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

  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

  10. 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

  11. 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

  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

  13. 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

  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 )

  16. 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

  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

  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 ) • 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

  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 = 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

  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 ) 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 timeinto the urine container. This completes the collection. • If possible, keep the urine specimen refrigerated.

  24. Reference range • 97 - 137 ml / min ( male) • 88 - 128 ml / min (female) • Let’s remember 90 - 130 ml / min

  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 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

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