Conference 05 - 2011 Case: 04 20111005

Signalment:

20-year-old American Paint mare (Equus ferus caballus).This icteric horse presented with anemia, and renal failure and hemoglobinuria, were noted on clinicopathologic evaluation. Despite transfusion of eight liters of blood, supportive care, and diuresis, renal values continued to increase and the animals clinical condition continued to decline. Twenty-four hours prior to euthanasia, the animal was anorectic and had no fecal output.

Gross Description:

All tissues were discolored tan/yellow (icterus), with pallor of all organs (anemia). The kidneys were swollen and bulged on section (N11-296A, nephrosis). Compared to other pale organs, the kidneys were dark and brown urine was in the urinary bladder (hemoglobinuria).

Histopathologic Description:

Kidney: Segmentally, proximal tubules are variably distended and lined by attenuated, pale, basophilic epithelium with variably sized nuclei that are large and vesiculate with a prominent nucleolus. Some tubule are lined by necrotic and apoptotic cells, a few tubules have proliferation of cells with many nuclei/cells, and a few scattered tubules are lined by a simple, tall/cuboidal epithelium with occasional mitoses (tubular degeneration, necrosis and regeneration). Many distended lumens contain granular casts (Perls negative) that sometimes have admixed, smooth hyalinized foci and often contain degenerating neutrophils (heme pigment casts). Many less affected proximal tubules are lined by swollen epithelium and contain a pale eosinophilic acellular content. In these tubules the content stains pale blue with Fe stain (Perls/Prussian blue reaction), and the cells contain Fe-positive stippling. The interstitium and perivascular areas are pale and expanded (edema) with foci that are hyalinized and eosinophilic (fibrin, presumed) and large, reactive stromal cells. Many sloughed cells are in lower nephron tubules and collecting ducts with granular casts, fewer degenerating neutrophils and acid hematin (Perls negative) clumping, and interstitial edema is obvious.

Morphologic Diagnosis:

Subacute, segmental tubular nephrosis with tubular degeneration necrosis and regeneration, karyomegaly, and granular casts with edema.

Lab Results:

Hemogram

Leucocytosis with absolute mature neutrophilia (28975 {2260-8580})

Mild absolute monocytosis

Mild lymphoctosis

2+ eccentrocytes

Serum = 4+ hemolysis

Creatinine kinase 4683U/L (73-450)*

Aspartate aminotransferase 2246U/L (134-643)*

Total protein 11.6 g/dl (5.3-7.3)*

BUN 58mg/dl (7-28)

Creatinine 4.3mg/dl (1.1-2)

Total bilirubin 10.3mg/dl (<4.1)*

* tests can be falsely elevated when hemolysis >2+

Condition:

Red maple leaf toxicity

Contributor Comment:

This slide has most of the changes imaginable with tubular nephrosis, especially those of a nephrosis from hemoglobinemia. The horse had exposure to red maple limbs with leaves that had fallen after a wind storm over a week before presentation, and identifiable pieces of red maple leaves (N11-296B) were found in the colon.(1) Contact with wilted red maple (Acer rub rum) leaves and the presentation with hemolytic anemia, hemoglobinuria, icterus, Heinz bodies or eccentrocytes (methemoglobin) and some degree of renal failure are characteristic.(1-14) Apparently, methemoglobin is not often quantitated to show defective oxygen carrying capacity, and our lab did not do new methylene blue staining, so Heinz bodies were not described. Many cases are published and most do reference renal failure, and although some report deaths, many horses survive (dose response, presumably). Our horse could not be stabilized and clinically was considered to be in renal failure. The renal lesion certainly is a joy for the pathologist. Features of interest to pathologists in red maple toxicity are:

the kidney was/is remarkably preserved despite autolysis in other tissue
note where the iron metal stains
it is a segmental nephrosis
the karyomegaly often is not emphasized.(6)

The toxic principle is in wilted leaves, and its identity is unknown. Gallic acid is one of the usual suspects as an oxidant, and Vitamin C (and steroids) is recommended for treatment.(1,8) The combination of intravascular hemolysis, hemoglobinemia and hypoxemia make the renal lesion. Reasonable differential diagnoses include: onion toxicity (we have cases of wild onion toxicity in horses but it is milder), nitrite intoxication (iatrogenic), equine infectious anemia (fever), babesiosis (fever and parasites visible) and immune mediated hemolytic anemia (agglutination positive). We have had cases associated with silver maple.

JPC Diagnosis:

Tubular degeneration, necrosis, and regeneration, diffuse, moderate with hemoglobin and cellular casts and scattered tubulorrhexis.

Conference Comment:

This condition is only described in equids, and is probably due to their decreased capacity to reduce methemoglobin. Damage to the kidney results from acute tubular ischemic necrosis secondary to hemolysis. Neither hemoglobin nor myoglobin are nephrotoxic by themselves, and neither will cause injury when injected into a healthy kidney; however, in an ischemic kidney either may increase tubular necrosis. Gallic acid contributes to the oxidative stress of erythrocyte membranes resulting in Heinz body formation and subsequent anemia and methemoglobinemia. Heinz bodies are 1-2um round protuberances on the erythrocyte membrane composed of denatured, precipitated hemoglobin.(1,3,5,7,13)

There are two forms of A. rub rum toxicosis: a peracute form that typically occurs late in the autumn and a hemolytic form which occurs in early autumn. The peracute form results in massive methemoglobinemia, tissue anoxia and sudden death. Gross lesions include brown discoloration of tissues and blood, and cyanotic mucous membranes. The hemolytic form causes Heinz body formation, and subsequent intra- and extravascular hemolysis, in combination with methemoglobinemia. Clinical signs include weakness, lethargy, depression, anemia, icterus, hemoglobinuria and hemoglobinemia. Gross lesions include icterus, serosal petechia and ecchymosis, brown discoloration of the kidneys, splenomegaly, pulmonary congestion and edema, and mild to severe centrilobular hepatic degeneration and lipidosis.(5,7,13)

Differential diagnoses for hemolytic anemia in horses include Leptospira bratislava, Babesia caballi and B. equip, and wild onion (Allium sp.), which cause intravascular hemolysis; equine infectious anemia and Anaplasma plasmaphagocytophilum cause extravascular hemolysis. Other causes of methemoglobinemia include nitrate poisoning, chlorate toxicosis, and drugs such as phenacetin and acetanilide. Additional causes of Heinz body anemia include onion consumption in cattle, horses, dogs, and cats; rape, kale, and turnip consumption in cattle and sheep; chronic copper toxicosis in sheep, cattle, and swine; zinc toxicity in dogs; selenium deficiency; and the urinary acidifier methylene blue in cats. Heinz bodies can also occur spontaneously in cats.(5,7,13)

References:

1. Alward A, Corriher CA, Barton MH, et al. Red Maple (Acer rubrum) leaf toxicosis in horses: A retrospective study of 32 cases. J Vet Intern Med. 2006;20:1197-1201.
2. Brockus CW. Erythrocytes. In: Latimer KS, ed. Duncan & Prasses Veterinary Laboratory Medicine Clinical Pathology, 5th ed. Ames, IA: John Wiley & Sons Inc; 2011:34-5.
3. Corriher CA, Gibbons DS, Parviainen, AKJ, et al. Compend Cont Educ Prac Veter. 1999;21:74-80.
4. Divers TJ, George LW, George JW. Hemolytic anemia in horses after the ingestion of Red Maple leaves. JAVMA. 1982;180:300-302.
5. Fry MM, McGavin MD. Bone marrow, blood cells, and lymphatic system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease.5th ed. St. Louis, MO: Mosby Elsevier; 2011:718.
6. George LW, Divers TJ, Mahaffey EA, et al. Heinz body anemia and methemoglobinemia in ponies given Red Maple (Acer rubrum L.) leaves. Vet Pathol. 1982;19:521-533.
7. Maxie MG, Newman SJ. Urinary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmers Pathology of Domestic Animals. 5th ed. St. Louis, MO: Saunders Elsevier; 2007:446-447.
8. McConnico RS, Brownie CF. The use of ascorbic acid in the treatment of 2 cases of Red Maple (Acer rubrum)-poisoned horses. Cornell Vet. 1982;82:293-300.
9. Plumlee KH. Red Maple toxicity in a horse. Vet Hum Toxicol. 1992;33:66-67.
10. Semrad SD. Acute hemolytic anemia from ingestion of Red Maple leaves. Compend Cont Educ Pract Veter. 1993;15:2, 261-264.
11. Stair EL, Edwards WC, Burrows GE, et al. Suspected Red Maple (Acer rubrum) Toxicosis with Abortion in Two Percheron Mares. Vet Hum Toxicol. 1993;35:229-230.
12. Tennant B, Dill SG, Glickman LT, et al. Acute Hemolytic Anemia, Methemoglobinemia, and Heinz Body Formation Associated with Ingestion of Red Maple leaves by Horses. JAVMA. 1981;179:143-150.
13. Valli VEO. The hematopoietic system. In: Maxie MG, ed. Jubb, Kennedy, and Palmers Pathology of Domestic Animals. 5th ed. St. Louis, MO: Saunders Elsevier; 2007:254-255.
14. Warner AF. Methemoglobinemia and hemolytic anemia in a horse with acute renal failure. Compend Cont Educ Pract Veter. 1984;6:S465-8, S472.