HYALINE ACCUMULATION: OXALATE TOXICITY IN SHEEP


You're working for the state Extension Service in northern New Mexico and are asked to examine several sheep out at a local resident's subsistence farm near some BLM land where he grazes his livestock.

The farmer tells you that he had watered all the sheep in his flock early last week before turning them out to graze.  Since there is very little suitable forage, sheep in this region are allowed to graze far and wide in the company of dogs (to keep the coyotes away).  Several sheep crossed an arroyo and went on top of a small mesa and were unable to find their way down.  The farmer found them after a few days when he was out on the range to check out a water pump.  He managed to get them back to his farm but two died on the way back and the others look like they're in bad shape.

On physical examination you note seven weak, dehydrated, and twitching ewes.  Their sclera are congested, CRTs are prolonged, and their lower eyelids tent when pinched.  One of the ewes falls prostrate as you examine her.  Several of the ewes are oliguric in spite of their dehydration.

You immediately begin fluid therapy since the sheep must be quite dehydrated after several days without water.  While the fluids are running, you ask the farmer if he picked up the dead sheep.  He says no, but he knows where they are; it has only been about six hours, so the farmer drives out to get the carcasses for postmortem examination.

About an hour after you begin treatment, most of the sheep are looking only slightly better; the ewe that was prostrate looks much worse.  They're urinating more frequently and their twitching and staggering has increased.  A urine sample shows pronounced proteinuria on a dipstick test.  Your refractometer indicates the ewes' kidneys are not concentrating urine well.  They're dehydrated and suffering from renal failure, among other things.

A field necropsy on the carcasses shows the kidneys to have a mottled appearance implying infarctions.  The renal pelvises contain a whitish, gritty material as does one of the ewe's ureters.  On opening the rumen and you find a large amount of a scrubby, green plant with fleshy, succulent leaves. You have the answer to the situation.


DIAGNOSIS

Halogeton ( Halogeton glomeratus ) is a low, green, succulent plant that grows throughout the desert West of the United States.  It is often found on poor quality soil and waste areas such as overgrazed pasture.  Sheep and cattle are the most common victims of halogeton toxicosis although horses are occasionally affected. That's what has caused this problem.

The toxic principle in halogeton is a soluble oxalate that combines with serum calcium to form calcium oxalate crystals.  Formation of these crystals results in systemic hypocalcemia and formation of these crystals within the renal tubules can cause severe tubular damage.  Clinical signs of animals suffering halogeton toxicosis include muscle tremors and seizures (due to hypocalcemia) as well as depression, oliguria, azotemia and cardiac failure (due to renal failure).  Renal failure can be quite acute with death following rapidly.  In cases of more gradual toxicoses, the animal may develop a chronic glomerulotubular nephrosis and show signs of hyposthenuria, oliguria, and polydipsia.

These sheep died of a fatal renal toxicosis.  The signs of the toxicosis were masked by the more obvious signs of dehydration: dehydration led to decreased renal perfusion which exacerbated the effect of the toxin by allowing calcium crystals to form in kidneys which could not flush them out.  The white gritty material found in the ureters was calcium oxalate crystals.

Calcium oxalte crystals within the glomeruli disrupted the delicate filtration barrier that keeps protein from leaking into forming urine. What protein normally passes the barrier is recovered by the proximal tubules, but the protein load in these animals with damaged renal filtration is enormous, far beyond the ability of the PCT to recover. The result of this overload is formation proteinaceous hyaline casts downstream in the tubules.  Hyaline droplets are one of many signs indicating acute glomerular damage and are quite noticeable with a light microscope. They can occur whenever proteiuria is prolonged or excessive.


HISTOPATHOLOGY

This is the proximal convoluted tubule of a nephron in one of the dead sheep. The brightly eosinophilic droplets in the cells of the PCT are hyaline droplets, and the vast quanitity of hyaline present in these cells is an indicator of how impaired the protein filtration at the glomerulus for this nephron is. These PCT cells have taken protein in as fast as they can, in a frantic attempt to recover it: protein is metabolically expensive stuff, and no one wants to throw it away!

The problem is that they can't get rid of it as fast as they can accumulate it, and the constant, unending load of proteins flowing by has overwhelmed them. Normally small proteins (under 40 Kd) are lost to the filtrate, but the quantity is so small that the PCT can get it all back again and recycle it. In this case even the very large proteins that would be held back at the barrier are in the tubule, however.

The loss into the tubules of the nephron is so great that the proteins begin to precipitate out and form hyaline casts in the lumina. You can see this process, well under way, at right: the bright pink material in the lumen of these tubules is hyaline too.

The casts are gelatinous bits of coagulated protein that may be passed in the urine, and actually visualized, as you see at left. Note the conculted shape of this cast, which mimics that of the tubule in which it was formed.

Hyaline can be confused with another deposit, amyloid. Aside from their staining differences, amyloid is always deposited extracellularly, while hyaline isn't. Hyaline droplets form within the cytoplasm of the PCT cells.

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