Download Non-Protein Nitrogen (NPN) Compounds Objectives: After completion

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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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