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?

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 (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 from 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?

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 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 to learn about the nephrotic syndrome.


SELF-TEST QUESTIONS

Q1: What are the three forms of azotemia?
Click to see answer!
ANSWER: Pre-renal, renal, and post-renal.

Q2: List three reasons why the urine might be red. Click here for answer.
Click to see answer!
ANSWER: Blood, hemoglobin and myoglobin.

Q3: Outline the pathogenesis of these photographs taken at necropsy of a 13-yr-old dog.

Click to see answer!
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)

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