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Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected.

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Especially if you're looking for information on a disease with a name that you know, here are a couple of great places for you to go right now and use Medline, which will allow you to find every relevant current scientific publication. You owe it to yourself to learn to use this invaluable internet resource. Not only will you find some information immediately, but you'll have references to journal articles which you can obtain by interlibrary loan, plus the names of the world's foremost experts and their institutions.

Clinical Queries -- PubMed from the National Institutes of Health. Take your questions here first.
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GENERAL

Kidney problems are very common in clinical medicine. Essentially all seriously sick patients will need their kidney function evaluated during the course of their illnesses.

After history and physical exam are complete, the initial steps in checking patients' kidneys are performing a (1) urinalysis and obtaining a (2) serum creatinine and/or (3) serum urea ("blood urea nitrogen", "BUN") level. Next, you may check (4) ability to concentrate urine.

Both creatinine and BUN are included on the common chemical profiles. You can check the ability to concentrate urine using a hygrometer, refractometer, or dipstick.

Indications for these tests:

Newly discovered high blood pressure or diabetes

Abnormal urinalysis (anything more than "trace protein" or "honeymoon cystitis")

Any medical problem serious enough to admit the patient to the hospital

This section focuses on how to use blood tests to assess kidney function. Other units will introduce urine testing.

You should probably refer to a nephrologist when a man's creatinine exceeds 2.0 mg/dL, a woman's 1.5 mg/dL (NIH, 1993).

UREA ("BUN")

Urea, as you remember, is a relatively nontoxic substance made by the liver as a means of disposing of ammonia from protein metabolism.

*Urea has MW 60, of which 28 comes from the two nitrogen atoms.

Clinical chemists used to measure only the nitrogen in urea, hence the "urea nitrogen" measurement on lab reports.

The real concentration of urea is BUN x (60/28), or BUN x 2.14. But everyone thinks in terms of BUN units.

Normal blood urea nitrogen is 8-25 mg/dL (2.9-8.9 mmol/L).

Urea is filtered by the glomerulus. If the glomerular filtrate is flowing slowly through the proximal tubule, urea tends to be passively reabsorbed and return to the bloodstream.

Blood urea levels are quite sensitive indicators of renal disease, becoming elevated when renal function drops to around 25-50% of normal (remember the kidney has great functional reserve). The interpretation of the BUN is usually straightforward, though there are a few things to remember.

Increased BUN is, by definition, azotemia. It is due either to increased protein catabolism or impaired kidney function.

Increased protein catabolism results from:

• a really big protein meal (Kansas City steak, etc.)
• severe stress (myocardial infarction, high fever, etc.)
• upper GI bleeding (blood being digested and absorbed)

Impaired kidney function may be "prerenal", "renal", or "postrenal".

• Prerenal azotemia results from underperfusion of the kidney:

dehydration, hemorrhage, shock, congestive heart failure (review: NEJM 320: 397, 1989; but a poor guide to therapy, at least in kids: Ann. Emerg. Med. 18; 755, 1989); glomerulonephritis is likely also to be "prerenal" if mild, since it comprmises renal blood flow more than tubular function

• Renal azotemia has several familiar causes:

acute tubular necrosis, chronic interstitial nephritis, some glomerulonephritis, etc.

• Postrenal azotemia results from obstruction of urinary flow:

prostate trouble, stones, surgical mishaps, tumors

See below for some ways to distinguish these causes of azotemia.

In acute renal failure, BUN increases around 20 mg/dL each day (*estimates vary; range of increase is 10-50 mg/dL daily).

Decreased BUN

Lack of protein (celiac disease, some patients with nephrotic syndrome)

Severe liver disease (end-stage cirrhosis, yellow atrophy, really bad hepatitis, halothane or acetaminophen toxicity, enzyme defects)

Overhydration (iatrogenic, psychogenic water-drinking)

CREATININE

This breakdown product of creatine phosphate is released from skeletal muscle at a steady rate. (Only a small amount comes from meat in the diet.) Serum creatine correlates quite well with the percent of the body that is skeletal muscle.

It is filtered by the glomerulus, and a small amount is also secreted into the glomerular filtrate by the proximal tubule (hence at low GFR's, the usual reciprocal relationship breaks down and creatinine tends to underestimate how low the GFR has gotten).

If the urine volume goes up, the serum creatinine does go down slightly.

Creatinine is generally considered a somewhat more sensitive and specific test of renal function than BUN (for example, Arch. Dis. Child. 67(10SN): 1146, 1992; a more sensitive formula for "Cr-GFR" that takes into account a kid's height: Arch. Dis. Child. 64: 1261, 1989). * Bedside testing of serum creatinine using a reflectance meter: Br. J. Urol. 57: 510, 1985.

Normal serum creatinine is 0.6-1.5 mg/dL (53-133 micromoles/L). Whenever I've screened medical students, most of the women fall in the 0.6-1.0 range, most of the men in the 0.9-1.3 range. See also J. Lab. Clin. Med. 116: 327, 1990.

Increased creatinine is due to any cause of impaired kidney function listed above, a lot of meat in the diet, or a very large muscle mass (bodybuilders, anabolic steroid users, giants and acromegaly patients).

* A few drugs block the tubular secretion of creatinine, and will increase serum creatinine levels even though they have not damaged the kidney. This will be important if, and only if, the GFR is already very low. Remember probenecid, cimetidine, triamterene, trimethoprim, and amiloride.

In massive rhabdomyolysis / crush injury, there is so much creatine released that the creatinine will probably rise.

Athletes taking oral creatine may have slightly increases in serum creatinine levels for the next day or so, but the effect is slight and unlikely to take a person above the normal range (Br. J. Sports Med. 34: 284, 2000).

Decreased creatinine has little significance.

* A few medicines can falsely elevate the picrate Jaffe creatinine assay. High bilirubin levels can falsely lower serum creatinine values by some of the newer methods.

Because of the steady rate of creatinine excretion, substances in the urine are conveniently measured "per gram of creatinine". This is a reasonable alternative to 24 hour urine collection when we're not concerned about something that's produced sporadically.

Creatinine clearance (Br. Med. J. 293: 1119, 1986) is widely used to approximate glomerular filtration rate (which it does pretty well; Clin. Chem 35: 312, 1989; Arthr. Rheum. 33: 277, 1990). You need a timed urine sample and a blood sample.

You remember that the clearance of a substance is the volume of plasma "cleared" of that substance per unit time.

Clearance=(conc. in urine)x(urine volume)/(conc. in plasma). Derive this.

In deciding how to "time" your collection, remember that you don't really need to collect urine for a full 24 hours (heh heh). One group got more reliable results by a controlled collection over 4 hours, monitoring body position (kept them lying down) and hydration (Am. J. Ob. Gyn. 169: 576, 1993).

Creatinine clearance is not a perfect measure of GFR, because some is not filtered and some is secreted into the proximal tubule. These fractions tend to cancel each other out in health, but when GFR drops below 30 mL/min, tubular secretion approaches or even exceeds the amount filtered at the glomerulus (Surg. Gyn. Ob. 173: 279, 1991.

Reference range for creatinine clearance is 90-120 mL/min for young adults; values tend to fall by around 0.5 mL/year over age 20, worse for hypertensives (Nephron 47(S1): 62, 1987.

*Formulas to adjust "normal" for body surface area have been devised, etc. See Clin. Pharmacy 6: 399, 1987. For kids, a height/creatinine ratio of 2.1 or less is normal: Arch. Dis. Child. 64: 1261, 1989. GFR for adults can be estimated by various formulas; try 1.12xCrCl-20.6 (Clin. Pharm. Ther. 48: 503, 1990).

Whether or not "corrections" are applied, creatinine clearance is a pretty good estimate of glomerular filtration rate except at very low values, when tubular secretion of creatinine becomes proportionately greater. For these people, you can average creatinine clearance and urea clearance (remember urea tends to diffuse back through the tubules).

PRERENAL VS. RENAL AZOTEMIA

A very common clinical problem is to distinguish prerenal azotemia (due to shock, dehydration, CHF -- also "hepatorenal syndrome") from renal azotemia (acute tubular necrosis, "renal shutdown".)

Either could be the cause when a patient has been hypotensive and now is azotemic and oliguric. The management is different.

One older technique is to calculate the BUN/creatinine ratio.

This is normally around 10.

Values over 10, especially over 20, suggest prerenal azotemia rather than acute tubular necrosis. (Why? Figure it out yourself.)

High values are also seen postrenal azotemia and upper GI bleeding.

In fact, a high BUN/creatinine ratio is a common finding, especially in the elderly, and a marker for ill-health (delirium study Ann. Int. Med. 119: 474, 1993).

Another approach is to measure sodium on a urine specimen.

In prerenal azotemia, urine sodium is low (the kidney responds to low blood flow by "trying to retain all the sodium it can.")

In acute tubular necrosis, urine sodium is higher (the renal tubules are unable to concentrate or dilute the glomerular filtrate effectively.)

Urinary sodium under 20 mEq/L suggests prerenal azotemia (or hepatorenal syndrome, etc.); urinary sodium over 40 mEq/L suggests acute tubular necrosis.

*A further refinement, currently popular, is to measure the fractional excretion of filtered sodium, approximated by:



Values less than 1% indicate prerenal azotemia; values over 2% indicate acute tubular necrosis.

Several other factors can complicate the picture in such patients.

Diuretics will increase the excretion of filtered sodium, while secondary hyperaldosteronism (as in cirrhosis) will decrease sodium excretion.

In acute tubular necrosis due to myoglobinuria, sodium excretion is low (the tubules are plugged, not damaged.)

*Tip: If you obtain urine by squeezing a diaper or the absorptive balls you placed into the diaper, your estimate of urine creatinine will be low because these things absorb creatinine (Am. J. Clin. Nut. 55: 326, 1992).

Over a dozen variations on these bedside methods exist to tell you why your very-sick patient isn't making urine.

*Here are two popular ways of noting lab values in a patient's chart:

* LESS FAMILIAR RENAL FUNCTION TESTS

N-acetyl-beta-D-glucosaminidase ("glucosaminidase", NAG) is a lysosomal enzyme (MW 140,000) found in serum and urine. Urinary NAG is a proposed marker for tubular disease, especially subtle industrial poisoning, acute pyelonephritis, early acute tubular necrosis, and early transplant rejection. (Nowadays researchers seem to prefer beta-2 microglobulin).

The long ammonium chloride test checks for renal tubular acidosis type I (i.e., inability of the distal tubule to excrete a load of fixed acid). Ammonium chloride is administered orally and a person with "RTA I" supposedly will not be able to acidify the urine as low as pH 5.4.

Adenosine Deaminase Binding Protein is an enzyme from the brush borders of the proximal tubule. Like NAG, its presence in urine indicates tubular disease.

Urinary alkaline phosphatase in urine comes from the proximal tubular brush border (Radiology `82: 419, 1992).

Beta-2 microglobulin (beta-2-m) is the short chain of the HLA class I proteins. In health, it is freely filtered by the glomerulus, and fully reabsorbed by the proximal tubule.

Serum beta-2-m has been suggested as a measure of glomerular filtration rate, similar to creatinine. Obviously this isn't a good idea for patients with tissue necrosis, lymphomas, etc.

Urine beta-2-m has found widespread acceptance as an research tool. It appears if levels in the serum and glomerular filtrate exceed what the proximal tubule can reabsorb (more than 4.5 mg/L) or if there is renal tubular disease. It is very sensitive as an indicator of the latter. Review: Kid. Int. 32: 635, 1987.

Tubular functions: Urinary amino acids and maximum concentrating ability are sensitive screens for tubular damage. Lithium clearance is a researcher's way of estimating delivery to the distal tubule. You'll also read about urinary transthyretin (retinol binding protein: Arch. Dis. Child. 64: 1264, 1989) and atrial natriuretic peptide challenge. Don't worry about these now!

Isotope scans exist to compare the function of the kidneys (J. Nuc. Med. 28: 829, 1987). These may prove a valuable supplement to the intravenous pyelogram. More recently, the color Doppler sonogram, which is cheap and portable, has proved even more useful than these scans in transplant patients: Surg. Gyn. Ob. 173: 279, 1991. Most recent of all, there's a Tc99 scanner that monitors glomerular filtration minute by minute, suitable for the intensive care unit (J. Am. Soc. Neph. 4: 142, 1994, abstract 94214051).

Positron emission tomography is the latest way of measuring renal blood flow. See J. Urol. 150: 1064, 1993. Using the new scanners to calculate the glomerular filtration per unit volume of kidney: J. Urol. 165: 382, 2001.

SPECIFIC GRAVITY OF URINE

While not a "blood test", checking urine specific gravity provides very important information about tubular function and hydration.

People in our culture drink relatively little fluid. Thus "normal" people have fairly concentrated urine (SG greater than 1.010). Of course, the same is true of patients in prerenal azotemia (high urinary specific gravity, low or zero urinary sodium).

Patients with tubular disease ("renal azotemia", i.e., acute tubular necrosis, really bad bilateral pyelonephritis or interstitia nephritis, or on diuretics, or with end-stage kidney) will have isosthenuria.

Patients getting lots of fluid by IV, or with diabetes insipidus, or enthusiastic water-drinkers (asthmatics, crazies) will have low urine specific gravity.

URIC ACID

This breakdown product of purine metabolism is filtered by the glomeruli and both reabsorbed and secreted by the renal tubules. Serum levels are highly variable from day to day.

Indications for ordering this test include suspected gout and suspect uric acid nephropathy. However, it is generally measured as part of an automated chemistry profile.

Increased serum uric acid is often seen in:

• renal failure
• gout (remember all patients with gout have hyperuricemia, but most patients with hyperuricemia do not have symptomatic gout)
• liver-and-sweetbread gourmets ("organ meats" are rich in purines)
• increased breakdown of nucleoprotein (burns, crush injuries, very severe hemolytic anemia, plasma cell myeloma, myeloproliferative disorders, and especially leukemias under treatment)
• lead poisoning (why?)
• patients receiving thiazide diuretics or high doses of aspirin
• "idiopathic" (relatives of gout victims, etc.)

Low uric acid levels are of no concern (Nephron 51: 13, 1989). Remember that the average man has a higher average serum uric acid than the average woman.

TO THINK ABOUT:

1. Why is a decreased BUN seldom a finding of great interest to clinicians?

2. What are advantages and disadvantages of measuring a urinary substance "per gram of creatinine"?

3. What are the two reasons that upper GI bleeders have increased BUN?

4. What is the pathophysiology behind the use of the BUN/creatinine ratio?

5. What is the pathophysiology behind the use of the fractional excretion of filtered sodium? How is the approximate formula derived?

6. Why is uric acid usually included on the routine chemical profile?

Drop by and meet Ed

Ed says, "This world would be a sorry place if people like me who call ourselves Christians didn't try to act as good as other good people ." Prayer Request

Teaching Pathology

PathMax -- Shawn E. Cowper MD's pathology education links
Ed's Autopsy Page
Notes for Good Lecturers
Small Group Teaching
Socratic Teaching
Preventing "F"'s
Classroom Control
"I Hate Histology!"
Ed's Physiology Challenge
Pathology Identification Keys ("Kansas City Field Guide to Pathology")
Ed's Basic Science Trivia Quiz -- have a chuckle!
Rudolf Virchow on Pathology Education -- humor
Curriculum Position Paper -- humor
The Pathology Blues
Ed's Pathology Review for USMLE I
Part I
Part II