Chronic Renal Disease and Failure (CRD, CRF)
Chronic renal failure is characterized by a progressive
destruction of nephrons. It is hypothesized that regardless of the inciting cause, after a
critical level of renal dysfunction has been reached, that renal damage will be self
perpetuating.
In the normal animal, not all
nephrons are being fully perfused at any one time. The "resting, non-working
nephrons" are the renal reserve and are called upon when the kidneys must perform
"extra work" or are "called into the work force" as nephrons are lost
to disease.
As CRD progresses, more and more nephrons are lost to
disease and the renal reserve diminishes until all remaining nephrons are working, all of
the time. The remaining nephrons hypertrophy and increase their
workload in attempt to maintain homeostasis for the animal and the patient is
asymptomatic. The workload per individual nephron is called the "single nephron
GFR" (SNGFR). The SNGFR in disease is greater than in health but collectively the
overall GFR of all the nephrons of both kidneys is reduced simply because fewer nephrons
exist. The increase in SNGFR is also called hyperfiltration.
The adaptive mechanism of increased workload per nephron
(hyperfiltration) is initially beneficial and initially prevents development of clinical
signs but with time, the adaptive mechanisms may contribute to clinical signs and to
progression of renal damage.
As renal disease progresses, the remaining nephrons show a
narrower range of response to changes in the environment. The nephrons attempt to respond
appropriately to changes in the environment but cannot abruptly respond as they were able
to do in a state of health. For example, if the animal has a sudden increase in the intake
of sodium in the diet, the nephrons will attempt to eliminate more sodium in the urine in
order to keep body levels of sodium constant. The nephrons may not be able to respond
completely to the change in sodium intake and sodium retension may occur. Conversely if
the sodium intake in the diet is gradually increased, over days to weeks, then the
remaining nephrons have time to adapt and will excrete excess sodium to maintain constant
blood levels.
Eventually the increased workload on surviving nephrons
reaches a point where they can no longer maintain homeostasis and the signs of renal
failure become apparent. When total nephron mass is reduced to 1/3 of normal, there is an
impaired ability to concentrate and dilute urine. When total nephron mass is reduced to
1/4 of normal azotemia develops.
The causes of CRF
are diverse but often by the time a diagnosis of CRF is made, the inciting cause is no
longer evident. Some potential causes of CRF include:
- congenital malformation of the kidneys
- chronic pyelonephritis
- renal ischemia due to vascular disease such as the
vasculitis of systemic lupus erythematosis
- immunologic injury such as that caused by immune complex
disease
- progression of ARF
Often the renal biopsy of patients with CRF discloses
nonspecific changes that are called end stage renal disease (ESRD) which is advanced,
generalized, progressive irreversible renal disease with no inciting cause evident or
chronic interstitial nephritis (CIN) which likewise indicates irreversibilty and unknown
cause.
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Because the kidneys perform so many diverse
functions the clinical signs of uremia are
polysystemic.
Acid-base
balance in CRF:
The diet yields acids that are normally renally eliminated
in order to maintain acid-base balance. Additionally the kidney must reabsorb bicarbonate
that is filtered by the glomeruli. Both the mechanisms for excreting acid and preserving
bicarbonate may be impaired resulting in systemic acidosis.
To some extent acidosis is buffered by mobilization of
minerals from the bone which contributes to development of renal osteodystrophy.
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Water balance:
CRF patients often have a negative water balance (another
way of saying they are often dehydrated). The polyuria and gastrointestinal losses from
vomiting and diarreha must be matched by increased water intake (polydipsia) in order to
remain normally hydrated. As CRF progresses, the patients become systemically depressed
and may drink less or may attempt to drink but drinking water may incite vomiting.
The following discussion describes a single nephron but the
concept can be extrapolated to the entire population of nephrons. The blood flow to the
nephron is via the afferent arteriole. The afferent arteriole supplies blood to the
capillary loops that make up the glomerulus. In a state of health ~ 1/4 to 1/3 of the
plasma which enters the capillary loops in the glomerulus enter the tubular lumen as
glomerular filtrate. The is called the filtration fraction:
filtration fraction = renal blood flow/ glomerular
filtration
The blood which does NOT form glomerular filtrate leaves
the glomerulus in the efferent arteriole which continues into the medulla of the kidney as
the vasa recta capillaries which run parallel to the tubular portions of the nephrons. In
health, solute (primarily urea and sodium) are deposited in the interstitium of the kidney
(the black dots in the schematic). These solutes make the interstitium hypertonic so that
there is a "stimulus" for water to leave the tubular lumen and enter the
interstitium. In health the water will enter the vasa recta capillaries as they leave the
kidney resulting in return of water to circulation.
As the overall GFR decreases, a greater amount of blood
leaves the glomerulus in the efferent arteriole resulting in increased blood flow in the
vasa recta capillaries. As blood flow increases, solute (urea and sodium) are
"washed" out of the interstitium so that it is no longer hypertonic and there is
less "stimulus" for water to leave the tubule and enter the interstitium for
subsequent reabsorption. This is called medullary washout.
Additionally the increased amount of solute handled by a
smaller number of nephrons osmotically results in more fluid loss.
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Secondary
hyperparathyroidism and renal osteodystrophy
Bone lesions occur as a consequence of long term elevation
of parathyroid hormone and as a consequence of bone buffering of metabolic acidosis.
Parathyroid hormone (PTH) is secreted by chief cells of the parathyroid gland.
 |
| The effect of PTH on bone is to
mobilize both calcium and phosphorus. The full effect of PTH's action on bone requires the
presence of vitamin D. |
The effect of PTH on the gi tract
is to increase the uptake of both calcium and phosphorus. The full effect of PTH's action
on the gi tract requires the presence of vitamin D. |
The effect of PTH on the kidney is more
"discriminating". PTH increases tubular Ca reabsorption (decreased excretion)
and decreases tubular phosphorus reabsorption (increased excretion). |
PTH also stimulates the activation of vitamin D by the
kidney to the active form, (1,25 dihydroxycholecalciferol).
Secondary hyperparathyroidism (increased levels of PTH) is
the price paid (the trade-off) for maintenance of phosphorus and subsequently calcium
levels.
Progressive nephron destruction results in a decrease in
total GFR which results in a transient increase in serum phosphorus. Increased phosphorus
causes reduction in serum ionized calcium by simple mass action (as P increases Ca
decreases). Reduction of ionized calcium is the stimulus for the chief cells of the
parathyroid gland to increase PTH production. PTH leads to increased kidney reabsorption
and intestinal reuptake of Ca, and a return ot serum P and Ca to normal. A new steady
state is reached with higher serum levels of PTH.
As GFR steadily falls with progressive disease, PTH levels
continue to rise. Serum Ca levels are usually normal until terminal states. The response
of the parathyroid glands is appropriate as it is properly responding to the stimulus of
low Ca.
With time, some patients will develop
autonomously functioning parathyroid glands which do not respond to the return of serum Ca
to normal and continue secreting PTH resulting in hypercalcemia. Some call this tertiary
hyperparathyroidism which is not common in dogs and cats as they usually don't
live as long with renal disease as do people who can be maintained by dialysis and
transplantation.
As functional renal mass declines to 10-15% or normal,
active vitamin D is no longer produced, thus reducing intestinal Ca uptake and
mobilization of Ca from bone resulting in a low serum Ca and further stimulation of PTH
release
 |
Clinical signs that may be
attributable to PTH include:
- soft tissue calcification which can manifest as pruritus
- metabolic bone disease (renal osteodystrophy)
- anemia due to marrow fibrosis as a consequence of cortical
bone remodeling encroaching upon the marrow cavity. PTH also increases the fragility of
RBC making them more susceptible to lysis.
- neuromuscular disturbances. PTH has been shown to cause
disturbances in the electrical activity in neurons and muscle cells leading to mental
dullness/lethargy and muscle weakness
- decreased reabsorption of amino acids
- anorexia. PTH causes a state of partial insulin resistance.
Blood glucose levels are mildly increased which gives the animal the sensation of not
being hungry.
- PTH impairs both cellular and humeral immunity which
predisposes CRF patients to infections.
- PTH can contribute to the progression of renal dysfunction.
|
 |
 |
| The bony changes of renal
osteodystrophy can be subtle or striking. As bone mineral is reabsorbed under the
influence of PTH, fibrous tissue may be deposited in an attempt to
"strengthen" the bone weakened by loss of mineral. The most marked gross
changes in bone structure occur in young dogs. |
The bones may become more
flexible due to loss
of mineral: "rubber jaw" |
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Anemia of CRF is
nonregenerative, normocytic and normochromic. It is caused by deficiency of erythropoietin
releasing factor, erythroblast inhibition, reduced survival of RBC, iron deficiency (blood
loss, impaired absorption), myelofibrosis, chronic infection, or loss due to coagulation
abnormalities.
Coagulation
abnormalities arise from abnormal function of normal numbers of platelets
which is called thrombocytopathia.
Sodium handling
by diseased kidneys: The kidneys still try to maintain sodium balance by excreting excess
or conserving in states of limited intake. Each nephron must excrete more sodium to
maintain balance and there is a narrower range of response which leads to an inability of
the chronically diseased kidney to adapt to rapid changes in sodium intake (increases or
decreases).
Blood presure: Renal
failure patients are often hypertensive. Hypertension is defined as a systolic pressure
> 180 mmHg (dog) > 200 mmHg (cat) and a diastolic pressure > 95 mmHg (dog) >
145 mmHg (cat).
Blood pressure can be measured by
indirect techniques using oscillometric or doppler methods from the cranial tibial/dorsal pedal artery, metacarpal artery or the coccygeal
artery. Indirect readings are comparable to direct measurements obtained by arterial
puncture.
Blood pressure monitoring equipment is not uniformly
reliable in dog sand cats. Several readings should be obtained to confirm consistency of
the measured values.
 |
doppler blood pressure unit -
measures systolic
pressure only |
  |
| Dinamap oscillometric blood
pressure and inflatable cuffs for Dinamap. The cuff size must be appropriate for the size
of the patient or the readings will be inaccurate. |
Normal blood pressure in dogs (direct technique)
- 148 + 16 mmHg systolic
- 87 + 8 mmHg diastolic
- 102 + 9 mmHg mean
Normal blood pressure in cats (direct, awake, 5-10 mmHg
lower under anesthesia)
- 171 +/- 22 mmHg systolic
- 123 +/- 17 mmHg diastolic
- 149 +/- 24 mmHg mean
50-93% of dogs with renal failure are hypertensive. 80% of
dogs with glomerular disease are hypertensive. Hypertension may play a role in the self
perpetuation of renal failure. Hypertension can also cause cardiac disease, CNS
dysfunction and retinal detachment leading to blindness.
Factors which contribute to hypertension include:
- failure to excrete salt and fluid
- stiffening of venous capacitance vessels
- altered adrenergic activity
- activation of renin-angiotensin-aldosterone system
- suppression of renodepressor prostaglandins
Other ionic disturbances may be present
including an increase in magnesium which can cause drowsiness and increased neuromuscular
excitability. Potassium is variable depending on urine output, dieatary intake and
gastrointestinal losses but is usually normal or low in polyuric CRF. Cats may
develop a painful myopathy as a result of hypokalemia.
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Diagnosis of CRD and CRF:
The history is often nonspecific including signs such as
polyuria & polydipsia, nocturia/incontinence, gastrointestinal signs, anorexia, or
depression.
On physical examination, dehydration,
weight loss, pale mucous membranes, oral ulcers, palpably small kidneys, pathologic
fractures or loose teeth may be seen. Oral ulcers are due to the breakdown of urea present
in saliva to ammonia by oral bacteria. Hypertensive animals may present with acute
blindness caused by retinal detachment.
Hematology often discloses
nonregenerative, normochromic normocytic anemia and normal or a stress leukogram. CRF
patients may have impaired phagocytic function of neutrophils which may lead to infection
and leukocytosis. Anemia may be masked by hemoconcentration (dehydration). Platelets are
normal in number but abnormal in function which can lead to bruising at the venipuncture
site or other abnormal bleeding.
Biochemical changes include
- increased BUN
- increased creatinine
- increased phosphorus
- Na+ and Cl- usually normal but total
body concentration may be increased or decreased
- Ca is usually normal until terminal stage (may be low
terminally) unless hypercalcemia caused the renal disease in which case calcium will be
increased
Urinalysis will disclose a specific
gravity between 1.007-1.017 (Isosthenuria). Proteinuria is variable and is most
often seen in patients with congenital CRD and those in which glomerular disease is the
cause of CRF. The urine sediment is usually normal.
Radiology may show a decrease in kidney
size, with irregular contours. If the animal is in poor body condition, the absence of
abdominal fat may make visualization of the kidneys difficult. Contrast studies of the kidneys are NOT indicated.
Decreased bone density may be appreciated on the radiographs.
Renal
function tests are not necessary if the patient is azotemic. Renal
biopsy is often low yield in patients with CRF and is not necessary to make a
diagnosis. Renal biopsy is of value to make a diagnosis of congenital
renal disease.
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Treatment of CRF
The uremic crisis should be managed similar to the patient with ARF. Any prerenal influences should
be corrected with fluid therapy. Prerenal insults may precipitate a uremic crisis in a
previously compensated CRF patient.
Specific therapy of causative disorders may slow or stop
the development of renal lesions including correction of hypercalcemia causing hypercalcemic nephropathy, antibiotics to
eliminate bacterial infection, antifungals to eliminate mycotic infections, removal of
obstructions (e.g., uroliths or neoplasms), or correction of abnormal renal perfusion that
caused ischemia.
Diuretics are not indicated in the CRF patient unless they
are oliguric, and then only once the patient is rehydrated. Intensive diuresis protocols
using osmotic diuretics may be used if the patient becomes oliguric. See the ARF section for more specific information.
Conservative medical management is
formulated to maintain fluid, electrolyte, acid-base, endocrine, and nutrient balance by
providing unlimited access to water, decreasing the quantity of metabolic wastes to be
excreted by the kidneys and to provide metabolites that the kidneys cannot effectively
conserve or produce. This regime is conservative with respect to the cost and effort
required compared to more aggressive forms of therapy such as agressive fluid therapy or
dialysis. Conservative medical management is indicated when the clinical
signs of renal dysfunction are not severe enough to warrant more intensive forms of
therapy and after successful treatment of the uremic crisis by more intensive measures.
The initial response to conservative therapy may be relatively slow, taking weeks to
months to see a response.
Conservative medical management of CRF includes:
- unlimited access to water
- avoidance of stress and increased renal work ( changes in
the environment, nephrotoxic antibiotics, corticosteroids)
- avoidance or correction of circumstances which cause
dehydration and prerenal azotemia (e.g. unnecessary surgical episodes, vomiting, diarrhea)
- modification of dietary protein intake
- phosphorus restriction
- control of blood pressure
- water soluble vitamins
- normalization of acid base status
- correction of anemia
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Modification of dietary protein intake: It
is generally agreed that reducing dietary protein intake can ameliorate some of the
clinical signs of uremia. The controversial aspects of protein modification include when
to restrict protein, how much protein is needed, and will protein restriction delay the
progression of renal disease? Some studies in rats, humans and dogs demonstrate that high
protein diets result in glomerular hyperfiltration that in turn contributes to progression
of deterioration in renal function suggesting that protein restriction in patients with
CRD may ameliorate glomerular hyperfiltration and delay disease progression. This is not
accepted universally regarding dogs with renal failure (see Finco 1989 in Current
Veterinary Therapy X).
The optimal dietary protein requirements for dogs and cats
with CRF are not established. Current recommendations for patients with mild to moderate
CRF (Creatinine 1.5 - 4.5 mg/dl):
- Dogs - 2.0 -2.2 g/kg high biologic value protein
- Cats - 3.3 - 3.5 g/kg high biologic value protein
The protein source determines the biologic value and
usability of the protein. Proteins with high biologic value can be readily converted to
body proteins with minimal waste production. Animal proteins have a higher biologic value
than vegetable proteins. Eggs have the highest biologic value.
Protein modification can be achieved with homemade diets or
commercial diets such as Hills KD and UD.
- Feline KD - 29-30% of dry matter is protein
- Canine KD- 15-16% of dry matter is protein (maintenance
diets- 15 -25% protein)
- UD - 9.5-10.4% of dry matter is protein
The goal is to achieve the best compromise between dietary
control of clinical manifestations of uremia and prevention of malnutrition. Dietary
protein intake must be individualized to meet patient needs. The potential advantages of
protein restriction include reduction of nitrogen containing wastes, possibly slower
progression, and lower phosphorus intake which may slow the development of renal
osteodystrophy.
Potential disadvantages of protein restriction include
protein malnutrition characterized by weight loss, reduction in muscle mass, reduced PCV,
and reduced albumin. Protein restricted diets are less palatable than higher protein
diets. Dogs with CRD that are still eating are more likely to accept a change in diet to a
protein restricted diet than are dogs who are very ill and refusing most foods.
Protein restricted diets are more expensive than higher protein diets.
Adequate calories from fat and carbohydrate sources must be
supplied to prevent the ingested protein from being catabolized for energy. The minimum
caloric intake recommended is 60-100 Kcal/kg/day for dogs and 70-80 Kcal/kg/day for
cats. Warming foods may enhance their palatability.
Water soluble vitamins like B and C are
lost through diuresis and may need to be supplemented. Commercial diets sold for patients
with renal disease contain increased amounts of water soluble vitamins so additional
vitamins do not need to be given.
Phosphorus restriction may delay the
progression of renal failure and will minimize hyperparathyroidism. Protein restricted
diets are also restricted in phosphorus. If phosphorus remains increased while feeding a
protein restricted diet, phosphate binding agents which bind phosphorus in intestinal
tract can be administered. Phosphate binding agents include aluminum carbonate, aluminum
hydroxide, calcium citrate and calcium carbonate. Phosphate binding agents are given with
meals and are dosed to effect to normal serum phosphorus levels. Side effects may include
hypophosphatemia, constipation, and aluminum toxicity. Aluminum toxicity causes
encephalopathies and bone disease in humans, neither of which have been documented in cats
or dogs. Calcium containing phosphate binding agents should not be used until serum
phosphorus is reduced to < 6 mg/dl.
Calcium levels may be controlled by
controlling hyperphosphatemia. Active vitamin D or calcium supplements may be given if
hypocalcemia persists but only when hyperphosphatemia has been controlled. When Ca x P
product exceeds 70, calcium-phosphate salts will precipitate in soft tissues including the
kidneys.
Sodium bicarbonate should be administered
if serum bicarbonate is < 12mEq/L. The goal is to increase serum bicarbonate to
~18-28mEq/L. . Sodium bicarbonate should be administered cautiously in patients with
cardiac disease or hypertension. Bicarbonate precursors including calcium or potassium
salts of acetate, gluconate, lactate or citrate can also be used to alkalinize the
acidotic patient.
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Sodium restriction: The current
recommendations are for normal (800 mg sodium/100 g dry weight diet) or moderately reduced
sodium intake (250 mg sodium/100 g dry weight of diet). Diseased kidneys cannot
adapt rapidly to abrupt changes in sodium intake. Make changes in sodium intake gradually
over several weeks. Severely restricted sodium diets (< 200 mg sodium/100 g dry weight
of diet) may promote volume depletion and should not be used.
Treatment of hypertension: An attempt
should be made to confirm hypertension by measuring blood pressure.
Hypertension may be treated with:
- reduced sodium intake (0.1 - 0.3% of diet) (10 - 40 mg/kg of sodium)
- diuretics can be used. furosemide is the diuretic of choice
- beta-adrenergic antagonists (propanolol)
-
alpha adrenergic blockers (prazosin)
-
vasodilator drugs (captopril or enalapril)
- calcium channel blocking drugs like verapamil or amlodipine
The effectiveness of treatment should be assessed through
serial measurements of blood pressure.
Anabolic agents may promote anabolism
(positive nitrogen balance) for patients in a positive caloric balance. They may also
increase renal production of erythropoietin, stimulate bone marrow stem cells along RBC
lines, increase production of RBC 2,3 DPG with a shift of the oxygen-hemoglobin
dissociation curve to the right to facilitate release of oxygen from hemoglobin to
tissues, enhance Ca deposition in bones, and stimulate appetite. In fact, anabolic agents
are usually ineffective in accomplishing any of the benefits ascribed to
them. Anabolic agents include testosterone, stanozolol (Winstral V), oxymetholone, and
nandrolone decanoate.
Treatment of anemia: When the PCV is ~20 in cats and ~ 25% in dogs, anemia
contributes to the clinical signs. Anemia can be treated by blood transfusion or the
administration of recombinant human erythropoietin.
Erythropoietin is very effective in increasing PCV but has the potential for adverse side
effects including:
-
antibody formation which suppresses endogenous
erythropoietin production but is reversible with cessation of use
-
hypertension
-
seizures
Erythropoietin is administered subcutaneously at a starting
dose of 50 to 150 U/kg three times weekly (100 U/kg is the most commonly used starting
dose). When PCV is ~33% in dogs or ~30% in cats the dose is reduced to twice weekly. A
maintenance dose of 50 to 100 U/kg one to three times weekly is usually required. Low
doses, 50 U/kg three times weekly should be used initially in patients with hypertension.
Use with caution in hypertensive animals.
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Supression of
PTH levels:
Elevated levels of PTH may play a role in the genesis of
many of the clinical signs of CRF patients and may also contribute to the progressive
nature of chronic renal dysfunction. The administration of low doses of 1, 25
dihydroxycholecalciferol (calcitriol) will supress PTH secretion by the parathyroid glands
with reversal of some of the clinical manifestations and possibly a resultant slowing of
the rate of progression of renal dysfunction. A survey was formulated to query 250
practicing veterinarians who treated 570 dogs and 1,360 cats with
low daily doses of calcitriol at 2.5 - 3.5 ng/kg as to their perceptions (and those of the
pet owners) as to the impact of calcitriol treatment on clinical signs.
The following results (along with others)
were reported in: Veterinary Clinics of North America, small animal practice, November
1996.
The authors advocated the early use of calcitriol in
patients with CRF. The protocol for use is as follows:
-
control hyperphosphatemia
-
obtain a baseline PTH from a pool of a few
days of plasma
-
administer 2.5 to 3.5 ng/kg/day calcitriol
-
monitor serum calcium at 1 & 2 weeks
- check PTH in 2 months
The half life of calcitriol is 4 - 6
hours and the biologic effect lasts 4 days. If hypercalcemia develops, cessation of
calcitriol administration will rapidly result in a decline in serum calcium.
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Modification of dietary lipids:
 |
There are several types of lipids derived from the diet:
- polyunsaturated plant origin lipids contain large amounts of
omega 6 fatty acids
- polyunsaturated fish origin lipids contain large amounts of
omega 3 fatty acids
- animal fats are primarily saturated and do not contain omega
3 or 6 fatty acids
|
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The omega 3 and omega 6 fatty acids are degraded to
different eicosanoids. Preliminary studies suggest that diets high in omega 3
polyunsaturated fatty acids preserve renal function in dogs with induced renal failure
whereas diets high in omega 6 fatty acids hasten decline
|
The following protocol for dietary lipid
modification is recommended:
Drug elimination
may be altered in the CRF patient as described in the section on ARF.
1. An EXCELLENT reference written by
Carol
and David DiFiori, owners of a cat who died of CRF
2. Nutrition and Chronic Renal Failure by
Dr.
Tony Buffington, the Ohio State University
3. Diets for
canine
renal failure patients by Dr. Tony Buffington, the Ohio State University
4. Diets for
feline
renal failure patients by Dr. Tony Buffington, the Ohio State University
5. A summary of responses of veterinary nephrologists to a
series of questions regarding CRF
in cats
Department of Veterinary Clinical Sciences
College of Veterinary Medicine
Washington State University
Pullman, WA 99164-7060
Telephone 509-335-0711
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College of Veterinary Medicine,
Washington State University, Pullman, WA,
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Copyright 1995-2001 Washington State University
Revised October 08, 2002
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