UREMIA AND CONSEQUENCES OF URINARY DISEASE

Retention of excretory wastes

Abnormal urination
Abnormal urine contents
Systemic lesions
Nephrotic syndrome

RETENTION OF EXCRETORY WASTES

One of the CONSEQUENCES of URINARY DISEASE is incomplete excretion of waste products.

Do you recall the definitions of azotemia and uremia?

AZOTEMIA is defined as excessive urea

or creatinine in the blood.

It may be due to several causes -- not

only renal failure!

UREMIA is the presence of urinary

constituents in the blood AND the toxic
condition produced by those constituents.

Thus uremic animals would be azotemic

AND have clinical signs or systemic lesions
caused by the retained waste products.

Dogs often have gastro-intestinal or

neurologic signs when they are uremic.
This dog is nauseous and depressed.

PRE-RENAL AZOTEMIA

This is 1 of the 3 forms of azotemia.

Pre-renal azotemia is due to conditions

which cause decreased blood flow to the
kidney.

Since blood does not perfuse through the

kidney, waste products are not removed.
The urine that is formed has a high specific
gravity (due to attempts to conserve
water).

Can you think of an example?

 ANSWER: Dehydration as seen in this
calf with severe scours is a common pre-
renal cause. Note the sunken eye which
tells you the calf is very dehydrated.

RENAL AZOTEMIA

This is another form of azotemia.

Renal azotemia is due to disease or

lesions in the kidney which interfere with
renal function. Since the kidney does not
perform its normal function of waste
removal, waste products are retained in
the blood. In addition, the kidney can no
longer concentrate or dilute urine, resulting
in a urine specific gravity similar to that of
the serum (isosthenuria).

Can you think of an example?

ANSWER: This dog does not have much functional renal

parenchyma. There are multiple renal cysts (black
arrows) and the cortex and medulla are thin and not
distinguishable. The pelvis is also dilated (white
arrow).
POST-RENAL AZOTEMIA

This is 1 of 3 forms of azotemia.

Post-renal azotemia is due to disease or

lesions in the lower urinary tract (post-renal
tract) which prevent excretion of urine.

Since little or no urine is excreted, toxic

wastes remain or are reabsorbed from the
urine into the blood.

Can you think of an example?

ANSWER: This dog has a transitional cell carcinoma of

the urethra (all that tissue in the blue circle). This is
obstructing outflow from the bladder which is on the
right.

ABNORMAL URINATION

Another CONSEQUENCE of URINARY

DISEASE is abnormal urination.

Do you recall the following

definitions?

ANURIA
 ANURIA is the absence of urine excretion.

Causes: Renal or post-renal lesions may

result in anuria.

OLIGURIA

OLIGURIA is reduction in the amount of urine

excreted.

Causes: Include pre-renal, renal, and post-

renal factors.

This dog is dehydrated.

POLYURIA

POLYURIA is the passage of abnormally

large amounts of urine.

This may be verified by catheterization and

collection so the amount may be quantified
(as shown here).

POLLAKIURIA

POLLAKIURIA is increased frequency of

urination (the amount may be normal).
DYSURIA

DYSURIA is painful or difficult urination.

STRANGURIA is the slow and painful

discharge of urine due to spasm of the urethra
or bladder.

ABNORMAL URINE CONTENTS

Another CONSEQUENCE of URINARY DISEASE is abnormal substances (or in excessive
amounts) in urine. Do you recall these definitions?

PROTEINURIA

PROTEINURIA is the presence of excess protein in the

urine. A small amount of protein normally is excreted each
day (<100 mg).

Causes: Proteinuria may result from pre-renal, renal or

post-renal abnormalities. The dipstick (shown here) may be
used as a screening test for proteinuria. Protein excretion
may also be expressed as the [urine protein/urine creatinine
ratio].

HEMOGLOBINURIA

HEMOGLOBINURIA is the presence of

hemoglobin in the urine. So, the urine is
red.

Causes: Conditions which cause lysis of

RBC will result in hemoglobinuria.

Note the dark discoloration of the urine in

this bladder.

MYOGLOBINURIA

MYOGLOBINURIA is the presence of

myoglobin in the urine.

Another term is AZOTURIA -- as seen in

horses with exertional rhabdomyolysis
(tying up; Monday Morning Disease).

This results from damage to skeletal

muscle with the release of myoglobin into
the blood (myoglobinemia) and subsequent
excretion in the urine (myoglobinuria).

Special tests are required to distinguish

myoglobin from hemoglobin.
GLUCOSURIA is the presence of glucose in the urine. The renal threshold for glucose is low,
and thus elevated blood glucose levels will result in glucosuria. There is an easy dipstick test for
glucose. Did you remember that glucosuria may result in emphysematous cystitis?

CRYSTALLURIA

CRYSTALLURIA is the presence of

crystals in the urine -- usually seen in the
sediment. These crystals may predispose
to urolithiasis.

PYURIA

PYURIA is pus in the urine -- or the

presence of inflammatory cells in the urine
sediment (neutrophils as seen here).

HEMATURIA

HEMATURIA is the presence of red blood

cells in the urine.

The erythrocytes may have originated

from the kidney, ureter, bladder or
urethra. Remember they may lyse if urine
concentration is dilute.

SYSTEMIC LESIONS

Let's use this visual to discuss some events in chronic renal disease.

These are tissues from a dog with chronic

renal failure (kidney, parathyroid gland,
thyroid gland).

What lesions can you identify?

Yes, the "pitted" surface of the kidney is indicative of scarring. Since scars are composed
of fibrous connective tissue, the lesion is CHRONIC. Is there another indication of chronicity in
this visual?

Yes -- the parathyroid gland is enlarged

(arrow). This is indicative of
hyperparathyroidism, which may result
from chronic renal disease.

How?

Answer:

Most animals with renal failure have hyperphosphatemia; because the GFR is decreased,
phosphorus is no longer secreted adequately. The excess phosphorus binds up calcium in the
serum, lowering ionized calcium. With reduced ionized calcium, parathyroid hormone (PTH;
parathormone) secretion is stimulated, causing calcium to be released from readily mobilized
stores in the bone (called osteoclastic bone resorption). On the other hand, diseased
kidneys have a reduced ability to synthesize calcitriol (the active form of Vitamin D).

Decreased hydroxylation from 25-hydroxycholescalciferol to calcitriol leads to decreased

intestinal absorption of calcium. In addition, calcitriol normally suppresses PTH secretion, such
that reduced calcitriol levels further increases PTH secretion. With time, this results in
parathyroid hyperplasia (renal secondary hyperparathyroidism).

Other associated conditions include fibrous osteodystrophy (renal osteodystrophy) and soft
tissue mineralization.

Parathormone secretion has a "TRADE

OFF" in renal disease -- this trade off has
good and bad consequences.

The good consequences are phosphorus

excretion and calcium reabsorption in
bone.

The bad consequences are changes in the

bone (fibrous osteodystrophy) as seen
in the maxilla of this dog which resulted
from the resorptive activities initiated by
parathormone.

Most dogs in renal failure do not develop clinically evident fibrous osteodystrophy as depicted
above. It does occur in some cases of chronic renal failure.

This lesion in the endocardium is also a

result of renal failure.

Can you name the lesion?

Answer:

This is an example of mineralization

secondary to renal failure and uremia. The
left atrium (as seen here) is a common
sight of soft tissue mineralization in renal
disease.

Does mineralization occur elsewhere in chronic renal disease?

 This is an example of PLEURAL
MINERALIZATION due to uremia.

Note the surface of the intercostal

muscles are covered by the mineralized
pleura. This is called uremic frosting.

This is an H&E stained section of lung

from a dog in renal failure. Note the dark
pink to purple foci (arrows) -- these are
foci of mineralization. The alveoli are also
flooded with edema fluid; this also occurs
with uremia and is also called uremic
pneumonitis.

This is an example of FIBRINOUS

PERICARDITIS with mineral deposition
secondary to uremia in a dog with renal
failure.

There are two possible mechanism to explain soft tissue mineralization associated with renal
disease:--

One mechanism is METASTATIC MINERALIZATION -- there is excess Ca and P in the blood --

the two combine and form mineral deposits in tissues near the site where they first combine. In
this pathogenesis, the mineral calcium phosphate forms due to excess levels of calcium and
phosphorus in the blood. Most experts believe another mechanism is more likely.

It is more likely that cells or tissues are injured FIRST and then become mineralized
SECONDARILY. This process is called DYSTROPHIC MINERALIZATION. For instance, the
stomach mucosal cells may be injured by a "uremic toxin"-- the toxin is not known (it might
even be the excessive Ca or P levels or parathormone itself). Once the cells are injured, a
cascade of events occurs which results in mineral deposition within the injured and dead cells or
tissue.

Do you remember another serious problem that occurs in the stomach secondarily to
renal failure?
 One of the lesions seen in uremic animals
is gastric ulceration and gastric
hemorrhage.

What two factors are involved?

 Secretion of ammonium ions

 Vasculopathy

Do you see the lesion and recognize

a sequela?

This is an example of FIBRIN deposition

in the wall of this gastric artery (so
called FIBRINOID NECROSIS).

In uremic animals, vasculopathy and

coagulopathy are seen. A common
sequela is thrombosis, vascular
obstruction and ischemic necrosis of the
mucosa supplied by the affected branch
of the artery.

Another lesion commonly associated with renal failure is shown below.

Note the oral ulcers (ulcerative

stomatitis).

Oral ulcers and ulcerative glossitis

may result from acute or chronic renal
failure.

This is an example of lingual ulcers

secondary to renal failure. They are often
seen on the underside of the tongue.
 Ischemic necrosis of the tongue also
may result from acute or chronic renal
failure

Again looking at this kidney, let's discuss another consequence of renal failure. We have
said the surface is pitted and scarred. What does this indicate is happening to nephrons?

The nephrons are being lost and replaced

by scar tissue.

The remaining nephrons compensate for

the loss. They do this by undergoing
NEPHRON HYPERTROPHY.

Remember the cardinal principle though; A LOST NEPHRON IS NEVER REPLACED WITH A
NEWLY REGENERATED NEPHRON -- we have a finite number of nephrons (we never get new
ones!). So compensation can occur within limits, but at a certain point the number of nephrons
lost exceeds the ability of the remaining nephrons to compensate by hypertrophy.

What happens at this point?

At that point functional deficits are seen;

the urine is not concentrated and wastes
are not removed from the blood.

The animal is in RENAL FAILURE with

chronic renal disease. Azotemia/or uremia
occur because 3/4 of the nephrons have
been lost.

What is the term for the kidney at this

stage?

Answer - ENDSTAGE KIDNEY

The term ENDSTAGE KIDNEY is used to describe renal disease which is chronic, advanced,
generalized, progressive and irreversible. The term was adopted because of the inability to
differentiate antecedent causes of "end stage kidneys". See the example below:

Can you determine the cause of these

lesions?

Not anymore.

In other words, the cause may have been

glomerular, tubular, vascular, or interstitial
- but the final gross appearance is the
same because fibrosis results from all of
these causes. Note these kidneys are
scarred and fibrotic - the cortex is nearly
absent in some areas.

In the example below, the end stage kidney was due to chronic glomerular disease. However,
we cannot tell the cause was glomerular by examination of a kidney at this late stage of
disease.

This dog died of renal failure (endstage

kidney) that was known to be due to
glomerular lesions.

Can you think of sequela that may occur

secondary to glomerular lesions (hint it is
a SYNDROME)?

How about the NEPHROTIC SYNDROME. Proceed to the next section below to learn about the
nephrotic syndrome.

SELF-TEST QUESTIONS

Question 1: What are the three forms of azotemia?

ANSWER: Pre-renal, renal, and post-renal.

Question 2: List three reasons why the urine might be red. Click here for answer.
ANSWER: Blood, hemoglobin and myoglobin.

Question 3: Outline the pathogenesis of these photographs taken at necropsy of a 13-

yr-old dog.
ANSWER: Renal fibrosis (end stage kidney) ⇒ chronic renal failure -> hyperphosphatemia and
depressed serum CA -> hyperparathyroidism -> pleural mineralization (metastatic
calcification)

OR

Renal fibrosis (end stage kidney) -> chronic renal failure -> uremic tissue damage coupled
with increased serum phosphorus and Ca levels -> pleural mineralization (dystrophic
calcification)
 NEPHROTIC SYNDROME

This dog has signs compatible with the

NEPHROTIC SYNDROME - a syndrome that
is seen with severe glomerular lesions.

What is one sign that is evident in this

view?

EDEMA is visible in this dog's face.

Would the edema be confined to the subcutaneous tissues of the head of an animal with the
Nephrotic Syndrome?

The clinician is examining the abdominal

skin of this dog.

Do you see a lesion?

Note the thumb print as evidence of pitting

edema.

The edema is generalized as seen in this

visual.

Can you think of a pathogenesis for the edema and the SYNDROME?

There are four components of the nephrotic syndrome: --

1. PROTEINURIA,
2. HYPOPROTEINEMIA,
3. EDEMA and
4. HYPERCHOLESTEROLEMIA.

Note that a common cause for these signs is increased permeability of the glomerulus. Damage
to the glomerulus would result in increased permeability, allowing protein to escape from the
blood into the glomerular filtrate. This would result in hypoproteinemia with subsequent edema
formation due to decreased oncotic pressure.

Hypercholesterolemia is thought to result from altered metabolism that occurs following the
protein loss.

There is a life threatening risk for animals with nephrotic syndrome.

Do you know the risk?

 A possible sequela is PULMONARY
EDEMA as demonstrated by the lungs from
this cat.

Why would pulmonary edema occur?

This horse is proteinuric, polyuric,

dehydrated and hypoproteinemic.

Do you recognize the danger involved in

the therapy (i.e., what is a possible
consequence of fluid administration)?

Because the animal is dehydrated AND hypoproteinemic, the addition of vascular fluids will
further dilute the plasma proteins. Thus edema would become more severe due to the
decreased plasma oncotic pressure. Pulmonary edema is a serious and often fatal
consequence. Uremic animals (especially proteinuric and uremic animals, those with glomerular
disease) are at risk for another fatal outcome. Do you remember this one below?

THROMBOSIS.

Note the pulmonary thrombus in this dog

that had severe glomerular amyloidosis
and proteinuria.

There are proteins which inhibit coagulation (i.e., Anti-thrombin III) that are lost in the urine of
proteinuric animals. Since they are depleted, inhibition of coagulation is decreased, and
thrombosis may result.

Can you think of some types of glomerular lesions (or diseases) that would result in the
NEPHROTIC SYNDROME?

Any alteration in the glomerular capillary wall may result in altered glomerular ultrafiltration.
Renal glomerular amyloidosis is one example of glomerular disease that can result in the
nephrotic syndrome. The amyloid deposits would alter glomerular ultrafiltration and result in
increased loss of protein (proteinuria).