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Non-Protein Nitrogen (NPN) Compounds Objectives: After completion of this lesson, the participant will be able to: 1. Explain the functions of the kidney to include the following: a. Excretory and reabsorptive functions: metabolic waste, dietary excess and essential substances b. Regulatory function: electrolyte, acid-base, and water homeostasis c. Endocrine function: erythropoietin and renin 2. State the function of each of the major components of the kidney 3. Describe the biosynthesis and excretion of the following nonprotein nitrogen compounds: a. Urea (BUN) c. Uric acid b. Creatinine d. Ammonia 4. Discuss the effects of the following variables to plasma urea (BUN) concentration: a. Protein in the diet d. Renal blood flow b. Protein metabolism e. Renal function c. State of body hydration 5. Discuss the effects of the following variables to plasma creatinine concentration: a. Diet c. Muscle turnover rate b. Muscle mass d. Renal function 6. Correlate creatinine clearance results to altered glomerular filtration rate and function 7. Discuss the effects of the following variables to plasma uric acid concentration: a. Diet c. Increased cell turnover b. Purine metabolism d. Renal disease 8. Briefly discuss preanalytical errors that will affect plasma ammonia levels 9. Discuss the toxic effects of increased plasma ammonia levels 10. Given patient values for urea, creatinine, uric acid and ammonia and supporting clinical history, suggest possible clinical conditions associated with the test results a. Acute renal failure (disease) d. Nephrotic syndrome b. Chronic renal failure (disease) e. Reye’s Syndrome c. Gout CLS 500 Application and Interpretation of Clinical Laboratory Data Informational Outline: Non-protein Nitrogen (NPN) Compounds 1 Significance of Non-Protein Nitrogen (NPN) Compounds I. Basic Anatomy of the Kidney A. Blood Supply 1. Blood supply is critical for normal kidney function 2. Receives approximately 25% cardiac output B. II. Components of the kidney 1. Nephron 2. Afferent and efferent arterioles 3. Glomerulus (filtration) 4. Bowman’s capsule and Bowman’s space 5. Tubules (reabsorption, secretion): PCT, Loop of Henle, DCT 6. Collecting ducts (tubules) Renal Function: formation of urine A. Excrete undesirable end products of metabolism: 1. Non-protein nitrogen compounds: urea (BUN), creatinine, uric acid 2. Organic acids, amino acids B. Reabsorb essential substances back into the bloodstream CLS 500 Application and Interpretation of Clinical Laboratory Data Informational Outline: Non-protein Nitrogen (NPN) Compounds 2 C. Maintain body homeostasis: 1. Electrolyte balance: sodium, potassium, chloride, calcium, phosphate 2. Acid-base balance: HCO3, ammonia, H+ 3. Water balance: effects of hydration status and ADH D. Endocrine function: 1. Primary: renin, erythropoeitin, prostaglandins 2. Secondary: produce vitamin D3 from dihydroxycholecalciferol Summary: Important Components of Renal Function III. Filtration Preparation of an ultrafiltrate Reabsorptive Glucose, amino acids, electrolytes, proteins Homeostatic Extracellular volume, acid-base status, blood pressure, electrolytes Metabolic Synthetic: glutathione, glyconeogenesis, ammonia Catabolic: hormones, cytokines Endocrine Erythropoietin, vitamin D, cytokines Excretion Toxins, end-products of metabolism Non-protein nitrogenous (NPN) compounds A. Catabolism of proteins and nucleic acids results in the formation of the so-called non-protein nitrogenous compounds. Several of these metabolic products are sequentially derived from the catabolism of either exogenous (dietary) or endogenous (tissue) proteins: 1. proteins Æ amino acids Æ ammonia Æ urea 2. purines and purine nucleosides (nucleic acids) Æ uric acid 3. creatine and creatine phosphate Æ creatinine B. Kidneys play a major role in excretion of these compounds C. Measurement of these compounds plays an integral role in the assessment of a patient’s renal status CLS 500 Application and Interpretation of Clinical Laboratory Data Informational Outline: Non-protein Nitrogen (NPN) Compounds 3 IV. Urea (blood urea nitrogen = BUN) A. Biosynthesis and Excretion 1. >75% of NPN excreted in urine is urea 2. Biosynthesis of urea from ammonia is carried out exclusively by the liver (urea cycle) Proteins Æ amino acids Æ ammonia Æ urea liver 3. 4. 5. 6. B. >90% of plasma urea is excreted by kidneys Urea is freely filtered by glomerulus, but 40-70% passively diffuses back to plasma through tubules Production of urea is dependent on several variables that limit its utility a. High protein diet b. Hepatic function c. Increased protein catabolism; muscle wasting (as in starvation) d. State of hydration: beyond the PCT, renal handling of urea is dependent on the state of hydration of the patient 1. Dehydration: plasma urea increased; urea clearance and excretion are decreased 2. Overhydration: plasma urea low; urea clearance and excretion are increased e. Post-renal obstruction of urine flow (prostatitis) Urine contaminated with bacteria that hydrolyze urea will cause a loss of urea (decreased urea level in urine) and consequent formation of ammonia with elevation of urinary pH Clinical Application: Measurement is considered a test of renal function 1. Expected values: plasma: 5 - 20 mg/dl (critical > 100 mg/dl) 2. Increased BUN levels a. Pre-renal causes resulting in decreased GFR: Congestive heart failure Shock Hemorrhage Dehydration Marked decreased blood volume, renal blood flow b. Renal causes: severe renal impairment, renal failure c. Post-renal causes (obstruction to flow of urine anywhere in the urinary tract): stones, tumors of bladder or prostate, severe infection d. Alteration in protein metabolism/intake: high protein diet, fever, stroke, major illness CLS 500 Application and Interpretation of Clinical Laboratory Data Informational Outline: Non-protein Nitrogen (NPN) Compounds 4 3. Decreased BUN levels: (uncommon) a. Low protein diet, malnutrition b. Newborn c. Severe hepatic insufficiency d. Severe vomiting or diarrhea e. Over hydration 4. Interpretation of plasma urea (BUN) values Urea (BUN) Interpretation 5-20 mg/dL Reference range 20-26 mg/dL Dehydration (creatinine normal) <8-10 mg/dL Overhydration 50-150 mg/dL Beyond variation expected from urine flow or nitrogen load - implies impairment of GFR Conclusive evidence of severe renal impairment 150-250 mg/dL 5. V. The principal clinical utility of plasma urea measurement is its measurement in conjunction with creatinine Creatinine (and creatine) A. Biosynthesis and Excretion 1. Creatine is synthesized mainly in the liver, and then transported in blood to other organs such as muscle and brain where it is phosphorylated to phosphocreatine, a high energy compound 2. A proportion of creatine in muscle (approx 1-2% per day) spontaneously and irreversibly converts to creatinine 3. The amount of creatinine produced each day is related to muscle mass and body weight and normally does not vary significantly from day to day 4. Plasma creatinine levels are fairly constant, although diet may influence plasma levels: high meat intake can alter results by as much as 10% 5. Creatinine is freely filtered by the glomerulus and is not significantly reabsorbed by the tubules B. Clinical Application: Measurement is considered a test of renal function 1. Owing to the constancy of formation and excretion, and because creatinine is endogenously produced, and because its plasma levels are maintained within narrow limits, creatinine levels are a useful index of renal function, primarily glomerular filtration rate (GFR) CLS 500 Application and Interpretation of Clinical Laboratory Data Informational Outline: Non-protein Nitrogen (NPN) Compounds 5 2. Expected values: Adult men Adult women serum 0.9 - 1.3 mg/dl 0.6 - 1.1 mg/dl urine 1000 - 1900 mg/24hr 800 - 1700 mg/24hr Plasma Creatinine Value Interpretation 4 mg/dL Reduction in GFR to 15% - 20% of normal 8 mg/dL Reduction in GFR to 6% - 10% of normal Incremental Increases: 1 to 3 mg/dL/day Complete cessation of glomerular function <1 mg/dL/day Glomerular function not totally impaired >3 mg/dL/day Increased release of creatinine into plasma; may be seen with muscle necrosis C. Creatinine Clearance (CrCl) 1. Clearance tests are used to evaluate glomerular function (glomerular filtration rate = GFR); also useful when evaluating/supervising the administration of nephrotoxic drugs: aminoglycosides, digoxin, guanethidine, sulfonamides, methotrexate, 5-fluorouracil 2. Clearance of a substance is the volume of plasma from which that substance is cleared per unit of time 3. Glomerular clearance of creatinine is evaluated because: a. creatinine is freely filtered by the glomerulus and is not appreciably reabsorbed by the tubules b. creatinine is produced by endogenous metabolism c. the amount of creatinine produced daily is relatively constant d. the amount of creatinine produced is directly related to body surface area 4. As renal function fails, the GFR decreases and the creatinine clearance decreases 5. Suggested to establish baseline GFR with CrCl, then follow with plasma creatinine levels 6. Specimen collection: timed urine (24 hr preferred) and concurrent blood specimen 7. Calculation: CrCl = (urine creatinine mg/dl) x (volume ml/min) (plasma creatinine mg/dl) 8. Can estimate CrCl (mL/minute/1.73 m2) using Cockroft and Gault algorithm: (140 - age in years) x 2.12 x weight (kg) x K Serum creatinine x BSA (m2) Where: K = 0.85 for women and 1.00 for men BSA = body surface area CLS 500 Application and Interpretation of Clinical Laboratory Data Informational Outline: Non-protein Nitrogen (NPN) Compounds 6 9. Expected CrCl values: Adult male Adult female 97 - 137 mL/minute 88 - 128 mL/minute Symptoms Associated with Falling Glomerular Filtration Rate (GFR) GFR (mL/minute/1.73 m2) Symptoms 125 - 152 Symptomless, except for those symptoms resulting from any underlying pathology Fatigue, diminished well-being; PTH elevated, Vitamin D reduced Anemia; metabolic abnormalities such as acidosis; calcium homeostasis deteriorates Nausea, vomiting, gastritis Cardiovascular and neurological symptoms End-stage renal failure; potassium homeostasis fails < 45 < 30 < 15 < 10 <5 VI Uric Acid A. Biosynthesis and Excretion 1. Uric acid is the major end product of purine (ex: adenosine and guanosine) nucleotide catabolism. Adenine and guanine nucleotides may be used as the building blocks of DNA and RNA, and high energy compounds ATP and GTP 2. The conversion of purine nucleotides to uric acid occurs mainly in the liver. 3. Virtually all uric acid is filtered through the glomerulus; but through a complex renal handling scheme, only 6-12% is actually excreted in urine. 4. Plasma uric acid levels will vary with: a. Dietary intake (excess purine consumption) b. Renal disease c. Excess purine synthesis B. Clinical Application 1. Expected values 2. males females 3.5 - 8.0 mg/dl 2.5 - 6.2 mg/dl Increased Uric Acid: a. Gout b. Seen in conditions involving increased cellular destruction. Massive destruction of cancer cells by cytotoxic agents causes release of large amounts of uric acid. Allopurinol is a drug that inhibits an enzyme in the uric acid synthesis pathway acting to keep uric acid levels low, but is nephrotoxic c. Hyperuricemia is commonly defined as plasma uric acid > 7.0 mg/dl in males and >6.0 mg/dl in females CLS 500 Application and Interpretation of Clinical Laboratory Data Informational Outline: Non-protein Nitrogen (NPN) Compounds 7 d. Asymptomatic hyperuricemia is often detected through screening. Long term follow-up of these patients is recommended because many are at risk for renal diseases as a result of the high uric acid levels; few go on to develop gout e. Hyperuricemia appears to be associated with risk of coronary heart disease Causes of Increased Plasma Uric Acid Gout Dehydration Acute Inflammation Hematologic Conditions: Leukemia Lymphoma Hemolytic Anemia Megaloblastic Anemia Infectious Mononucleosis Polycythemia Vera Chronic Renal Disease Drug Induced: Thiazides Salicylates (low dose) Pyrazinamide Ethambutol Nicotinic Acid Cytotoxics Tissue Necrosis Chemotherapy Malnutrition of All Types Therapeutic Radiation Alcohol Lead Poisoning Glycogen Storage Disease (type 1) Lactic Acidosis Toxemia of Pregnancy Psoriasis Lesch-Nyhan Syndrome Hypothyroidism Hypoparathyroidism 3. Gout a. A clinical disorder that occurs when monosodium urate precipitates from supersaturated body fluids (joint fluid and the tissue surrounding the joint) b. The deposits of urate are responsible for the clinical signs and symptoms. c. Wherever the deposits occur, an intense inflammatory response is elicited, a condition called gouty arthritis d. Gouty arthritis may be associated with deposits of urate crystals in joint fluid and surrounding tissue but can occur in other soft tissues as well. About 1 in 5 patients with clinical gout also have urinary tract uric acid stones 4. Decreased Uric Acid: a. Hypouricemia is less common, and is often defined as plasma urate < 2.0 mg/dl b. Causes include: 1. Severe alcoholism with liver disease (reduced purine synthesis) 2. Defective renal tubular reabsorption of uric acid 3. Drugs affecting renal transport pathways: thiazide diuretics, probenecid, phenylbutazone, high dose ascorbic acid, and high dose salicylates CLS 500 Application and Interpretation of Clinical Laboratory Data Informational Outline: Non-protein Nitrogen (NPN) Compounds 8 VII. Ammonia A. Biosynthesis and Excretion 1. As amino acids are deaminated, ammonia is produced Protein Æ amino acids Æ ammonia 2. The major source of circulating ammonia is the GI tract, where bacterial enzymes hydrolyze protein (glutamine) to ammonia. Portal-vein plasma ammonia is typically 5-10 fold higher than systemic circulation and hepatocytes typically metabolize this ammonia to urea for renal excretion. 3. Renal tubular cells are also able to generate ammonia from glutamine and other amino acids derived from muscle and liver cells. Ammonia is a gas that readily diffuses across cell membranes into the tubular lumen where it combines with hydrogen ions to form ammonium ions. Ammonium ions are not diffusable and are trapped in the tubular lumen and then excreted into urine with other anions such as phosphate, chloride or sulfate. B. Clinical Application 1. Ammonia exerts toxic effects on the CNS and disrupts acid-base balance 2. Unlike BUN, creatinine and uric acid (NPN), plasma ammonia levels are independent of renal function. However with renal failure, as BUN increases, more urea diffuses into the GI tract, where it is converted to ammonia. 3. Most common cause of increased plasma ammonia is severe liver failure (fulminant hepatitis) or chronic liver failure (cirrhosis) 4. Reye’s Syndrome, which is primarily a CNS disorder with minor hepatic dysfunction, is also associated with increased plasma ammonia 5. Inherited metabolic disorders (deficiencies of critical metabolic enzymes) are a major cause of increased ammonia levels in infants. 6. Fasting venous plasma ammonia concentration is useful in a. Differential diagnosis of encephalopathy when it’s unclear if it’s of hepatic origin. b. Diagnosing Reye’s syndrome c. Diagnosing inherited disorders of urea metabolism 7. Reliable measurement is dependent upon meticulous sample collection and handling: a. Anticoagulant: must be ammonia free (EDTA and heparin acceptable) b. No hemolysis, fasting sample c. Poor venipuncture technique (probing for a vein, using a heparin lock, drawing blood into a syringe and then transferring to anticoagulated tube, partial filling of anticoagulated tube) can falsely elevate plasma ammonia by 10-20 ug/dL d. Smoking is a source of ammonia contamination. The patient should not smoke after midnight before the morning of blood draw. One cigarette smoked 1 hour before venipuncture elevates plasma ammonia by 10-20 ug/dL. CLS 500 Application and Interpretation of Clinical Laboratory Data Informational Outline: Non-protein Nitrogen (NPN) Compounds 9 If the patient is a heavy smoker, he/she should shower before the test. All patients should have fresh pajamas on before blood is drawn. The technologist performing the test should be a non-smoker. e. 8. Production of ammonia in the evacuated tube by deamination of amino acids such as glutamine, is a source of ammonia contamination. Thus, specimen must be placed on ice immediately after blood draw and processed without delay Expected values: males:35-120 ug/dL females: 30-110 ug/dL VIII Renal Pathophysiology A. Screening for Renal Disease 1. Patients with renal disease generally present to the clinician because of an abnormality detected on a routine biochemical screen, a symptom or physical sign, or the patient has an underlying disease with known renal involvement such as diabetes mellitus 2. Routine urinalysis: Proteinuria 3. Microalbuminuria screening: should be performed on all suspected and diagnosed diabetic patients. 4. Plasma: decreased TSP, decreased albumin, increased BUN, increased creatinine 5. Azotemia a. Term describing any significant increase of NPN compounds (usually urea and creatinine) in the blood b. Also referred to as uremia B. Renal Failure 1. Often divided into acute or chronic condition, indicative of the rate at which damage occurs (rather than the mechanism that causes the damage) 2. Acute renal failure usually occurs in a hospital setting as a result of ischemic or nephrotoxic agents. CLS 500 Application and Interpretation of Clinical Laboratory Data Informational Outline: Non-protein Nitrogen (NPN) Compounds 10 Causes of Acute Renal Failure Cause Agents Pre-renal Hypovolemia Decreased effective plasma volume Decreased cardiac output Renovascular obstruction Interference with renal autoregulation Trauma, burns, surgery Nephrotic syndrome, sepsis, shock Congestive heart failure, pulmonary embolism Atherosclerosis, stenoses ACE inhibitors, cyclosporin Renal Glomerular and small vessel disease Agressive glomerulonephritis (e.g. post streptococcal, pre-eclampsia) Infection, infiltration, drugs, toxins Postischemic, nephrotoxins, hypercalcemia Interstitial nephritis Tubular lesions Post-renal Bladder outflow obstruction Ureteric obstruction Prostatism, neurogenic bladder Stones, blood clots, tumors, radiotherapy, retroperitoneal fibrosis Causes of Chronic Renal Failure Cause Agents Renal circulatory diseases Primary glomerular diseases Renal sequelae to metabolic disease Inflammatory diseases Renal obstructions Congenital renal deformity Miscellaneous conditions Renal vein thrombosis, malignant hypertension SLE, chronic glomerulonephritis Gout, diabetes mellitus, amyloidosis Tuberculosis, chronic pyelonephritis Prostatic enlargement, calculi Polycystic kidneys, renal hypoplasia Radiation nephritis Stages of Chronic Progressive Renal Disease Stage 1. Decreased renal reserve 2. Renal insufficiency 3. Renal failure 4. Uremic syndrome (end-stage) Renal Function Remaining (%) Serum Creatinine (mg/dL) Serum Urea Nitrogen (mg/dL) 50 - 75 25 - 50 10 - 25 0 - 10 1.0 - 2.5 2.5 - 6.0 5.5 - 11.0 > 8.0 15 - 30 25 - 60 55 - 110 > 80 CLS 500 Application and Interpretation of Clinical Laboratory Data Informational Outline: Non-protein Nitrogen (NPN) Compounds 11 C. The Uremic Syndrome 1. Term representing the terminal clinical manifestations of kidney failure 2. Pathophysiology a result of reduced GFR and decreased tubular function 3. Variety of renal diseases can progress to end-stage renal failure: a. Chronic glomerulonephritits b. Chronic pyelonephritis c. Immunological diseases with renal involvement (SLE) d. Obstruction in lower urinary tract e. Toxic or ischemic damage to tubules Signs and Symptoms of End-stage Renal Disease and Resulting Uremic Syndrome Symptoms of uremia (loss of appetite, nausea, vomiting, lethargy, muscle wasting, tremors) Disorders of micturition (frequency, nocturia, retention, dysuria) Disorders of urine volume (polyuria, oliguria, anuria) Alteration in urine composition (hematuria, proteinuria, bacteriuria, leukocyturia, calculi) Pain (an inconsistent symptom) Edema (hypoalbuminemia, salt and water retention) Electrolyte imbalance Abnormal mental function Evolves to stupor, coma, death if not provided hemodialysis or renal transplantation IX. Summary of Test Results: expected findings BUN Creatinine CrCl Uric acid Increased Increased Decreased Normal Increased Increased Decreased Increased Normal Normal Normal Increased Chemotherapy Normal End stage liver failure Reyes syndrome Normal Normal Increased Acute renal disease/failure Chronic renal disease/failure Gout CLS 500 Application and Interpretation of Clinical Laboratory Data Informational Outline: Non-protein Nitrogen (NPN) Compounds Ammonia Increased Increased 12