Signalment:  

8-day-old female alpaca (Vicugna pack).The cria presented with an abrupt onset of recumbency and illness. Clinically she was lethargic, febrile and has an elevated cardiac and respiratory rate. It was later revealed that she was being fed a powdered goat colostrum supplement.

Gross Description:  

A mildly autolyzed cria weighed 8.4 kg and was in thin body condition. She was mildly autolyzed. Mild, watery subcutaneous edema fluid was present in the fascia outside the ventral thorax. The abdominal cavity contained 300mL watery. Transparent, pale yellow fluid and an additional 30 ml similar fluid was present in the thorax. The lungs were mottled bilaterally, but floated in formalin. The left atrioventricular valve leaflets were diffusely opaque white. The kidneys were paler than expected and several milliliters of edema fluid surrounded each kidney. The abomasal mucosa was an intensely dark red.

Histopathologic Description:

In both kidneys, glomeruli are diffusely replaced by hard, readily fractured, intensely basophilic granular to homogeneous material consistent with mineral. The nuclei of mesangial cells can occasionally be made out in this material. Cortical tubular basement membranes are also frequently affected, occasionally along with basophilic stippling of tubular epithelial cells. In other parts of the nephron, tubular epithelial cells contain protein-rich casts or cytoplasmic hyaline droplets.

Additional mineralized areas were found in elastic arteries near the heart, trachea, compartment 3, spleen and adrenal.

Morphologic Diagnosis:  

Kidney: Metastatic calcification, renal glomeruli and tubules, severe.

Lab Results:  

Test	6 days of age	7 days of age	Normal values in llamas (Merck Veterinary Manual)
Glucose	160	ND	90-140 mg/dL
Urea nitrogen	180 mmol/L	183	13-32 mg/dL
Creatine	10.5	10.8	1.5-2.9 mg/dL
Sodium	147	149	134-150 mmol/L
Potassium	8.5	9.0	4.3-5.6 mEq/L
Chloride	110	112	106-118mEq/L
Albumin	1.7	2.0	2.6-4.7 mg/dL
Total protein	3.3	ND	5.6-7.3 mg/dL
Calcium	13.1	13.1	2.0-2.6
Phosphorus	13.4	14.6	4.4-8.5
AST	141	ND	10-280 IU/L
GGT	17	ND	5-29 U/L
CK	65	ND	10-200 IU/L

Condition:  

Vitamin D toxicity

Contributor Comment:  

Rickets is an important nutritional metabolic disease of young animals, attributed to deficiencies of vitamin D, calcium, phosphorus, or combinations of those elements. In camelids, low serum phosphorus may be associated with vitamin D insufficiency. Vitamin D bioavailability is considered low in these species.(6) The submitter estimated that the cria was fed supplement 3 times a day for a total of 6 days. If she fed one dose/ feeding, that would be a total of 49,500 IU total Vitamin D or 1,375 IU/kg/day (297,000 total IU or 8250 IU/kg). 

Rickets is considered a common clinical problem in camelids and is particularly frequent in crias born in September to March period particularly in the high latitudes of the northern and southern hemispheres. Prolonged inclement weather and conditions of reduced sunlight can be contributory to vitamin D deficiency under these conditions.(4) This animal was born in late August. Thus many owners supplement.

This cria was given a goat colostrum supplement fortified with vitamin D due to the owners concern that rickets was a possibility.(3) This supplement has been reported as a cause of hypervitaminosis D in alpaca crias previously. Among the signs found in other over-supplemented goats are hypercalcemia, hyperphosphatemia and renal dysfunction as seen in this case.

Metastatic calcification occurs in otherwise normal tissue due to hypercalcemia secondary to some disturbance in calcium metabolism. Entry of large amounts of calcium into cells results in its precipitation in organelles. Common causes are renal, vitamin D intoxication [commonly affects aorta, atrial and left ventricular endocarcium, lungs], elevated PTH or PTH-related protein, and neoplastic destruction of bone.(7) Common target tissues are gastric mucosa, kidney, lung, systemic arteries and pulmonary veins. Many of these cells lose acid and therefore have an alkaline internal compartment predisposing to deposition of mineral salts.

Calciferol and D3 localize in nucleus as do other steroids, turning on genes for increased calcium transport. In addition to being found in young animals due to vitamin overdose, as in this instance, pets ingesting Rampage rodent poison have similar lesions.

JPC Diagnosis:  

Kidney, glomeruli and tubules: Mineralization, diffuse, severe, with marked intratubular protein casts.

Conference Comment:  

The contributor provides an illustrative case of vitamin D-induced metastatic mineralization in the kidney of a cria, pairing it with a succinct synopsis of the entity. In conference, participants further explored the pathogenesis of this condition. As noted by the contributor, the renal mineralization in this case is an example of metastatic calcification, which is typically associated with hypercalcemia and/or hyperphosphatemia. In dogs, metastatic mineralization occurs if the calcium-phosphate solubility product, expressed in mg/dL, persistently exceeds 70. Conversely, dystrophic calcification occurs in normocalcemic animals in association with tissue damage, while calcinosis cutis is an example of idiopathic ectopic mineralization.(5)

Common causes of hypercalcemia include hyperparathyroidism, hypoadrenocorticism, acidosis, renal disease (in horses and some dog breeds), vitamin D toxicity, prolonged immobilization, osteolytic lesions, neoplasia (lymphoma, canine adenocarcinoma of the anal sac apocrine glands, plasma cell myeloma, some carcinomas), thiazide diuretics and granulomatous inflammation. Hyperproteinemia and hemoconcentration will also falsely elevate serum calcium.(2) Common causes of hyperphosphatemia include hemolysis, nutritional 2^o hyperparathyroidism, hyperthyroidism, hypervitaminosis D, osteolytic bone lesions, hypoadrenocorticism, renal failure (in most species except for horses), hypoparathyroidism, tumor lysis and administration of phosphate-containing fluids or enemas. Relatively high phosphorus is normal in young animals.(2) In this case, serum chemistry revealed both hypercalcemia and hyperphosphatemia, narrowing the differential diagnosis down to hypervitaminosis D, osteolysis or hypoadrenocorticism. The history of repeated vitamin D supplementation supports a diagnosis of renal mineralization secondary to vitamin D toxicity. The marked azotemia is secondary to renal failure, while hyperkalemia is attributed to renal failure or acidosis.

Although excessive dietary supplementation of vitamin D is the most frequent cause, ingestion of cholecalciferol-containing rodenticides or plants containing vitamin D glycosides (Cestrum dirunum, Solanum malacoxylon, Trisetum flavescens and Medicago saliva) have also been implicated in cases of vitamin D toxicity.(5) Vitamin D maintains plasma levels of calcium and phosphorus by acting on the small intestine, bone, and kidneys. Specifically, it promotes active uptake and transcellular transport of calcium by increasing calbindin synthesis; it stimulates renal calcium absorption in distal tubules; and it stimulates mobilization of calcium and phosphorus from bones. The latter occurs upon binding of osteoblast RANKL (receptor activator for NF-kB ligand) to preosteoclast RANK, which induces differentiation into mature osteoclasts and initiates bone resorption via secretion of HCl and proteases such as cathepsin K. Additionally, vitamin D contributes directly to mineralization of epiphyseal cartilage and osteoid matrix by stimulating osteoblasts to synthesize the calcium-binding protein osteocalcin, which is involved in mineralization of these matrices.(1)

Vitamin D is obtained directly from dietary sources or synthesized endogenously from a precursor (7-dehydrocholesterol) that is present in the skin. Irradiation of 7-dehydrocholesterol with ultraviolet light induces the formation of cholecalciferol (vitamin D3). The precursor in plants is ergosterol, which is converted to vitamin D2 by ultraviolet light and then converted to vitamin D3 in the body.(1) Inactive cholecalciferol (vitamin D3) binds to plasma α1-globulin and is transported to the liver. There, it is converted by hepatic 25-hydroxylases to 25-hydroxy-cholecalciferol (25-OH-D). Finally, renal α1-hydroxylase converts 25-OH-D to active 1,25-dihydroxycholecalciferol. Regulation of renal vitamin D production occurs through three major mechanisms. Hypocalcemia upregulates parathyroid hormone production, which induces activation of α1-hydroxylase and thus increases 1,25-dihydroxycholecalciferol production. Hypophosphatemia directly activates of α1-hydroxylase, resulting in a similar increase in 1,25-dihydroxycholecalciferol production. Conversely, increased levels of 1,25-dihydroxycholecalciferol provoke negative feedback inhibition of α1-hydroxylase.(1) New world monkeys are entirely dependent upon dietary sources of vitamin D since it cannot be synthesized in their skin and, as noted by the contributor, vitamin D availability is considered low in camelids, a condition which is exacerbated during the winter at high latitudes when ultraviolet radiation is decreased.(1)

References:

1. Dittmer KE, Thompson KG. Vitamin D Metabolism and rickets in domestic animals: a review. Vet Pathol. 2011:48(2):389-409.

2. Ferguson DC, Hoenig M. Endocrine system. In: Latimer KS, ed. Duncan and Prasses Veterinary Laboratory Clinical Pathology. 5th ed. Ames, IA: Wiley Blackwell; 2011:295-304.

3. Gerspach C, Bateman S, Sherding R, et al. Acute renal failure and anuria associated with vitamin D intoxication in two alpaca (Vicugna paco) cria. J Vet Intern Med. 2010;24:423-429.

4. McClanahan SL, Wilson JH, Anderson KL. What is your diagnosis? J Amer Vet Med Assoc. 2006; 229(4):499-500.

5. Thompson K. Bones and joints. In: Maxie MG, ed. Jubb, Kennedy, and Palmers Pathology of Domestic Animals, 5th ed. Vol. 1. St. Louis, MO: Elsevier Limited; 2007:10-11, 58-59.

6. Van Suan RJ. Nutritional diseases of llamas and alpacas. Vet Clin North Am Food Anim Pract. 2009;25(3):797-810.

7. Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis MO: Elsevier Mosby; 2012:40.

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3-1. Kidney

-2. Kidney

3-3. Kidney

3-4. Kidney

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