4-year-old, male castrated, Italian greyhound breed canine (Canis familiaris)This dog presented to the critical care service with a primary complaint from the referring veterinarian of possible toxicity and/or multi-organ failure. The owner reported that the night before presentation, the dog had vomited 18 times, and that since then the dog was listless and weak, and had not urinated since the onset of clinical signs. The dog was housed with three other dogs, including one who exhibited vomiting and diarrhea three days prior to this dogs illness but had recovered uneventfully.

Gross Description:  

Autolysis was moderate. The right and left kidneys were diffusely purple-black, and the urinary bladder contained approximately 1 ml of dark red urine. Petechial hemorrhages were present on visceral pleural surfaces of all lung lobes, and there was mild pulmonary edema. The peritoneal cavity contained approximately 150 ml of serosanguineous fluid. The entire gastrointestinal tract from stomach to rectum contained scant, tenacious, brownblack material resembling digested blood. The spleen was contracted, with an absence of blood in the red pulp.

Histopathologic Description:

Diffusely, most cortical distal tubules, collecting ducts, and medullary tubules contain extensive intraluminal casts (Fig. 1-1). Fewer casts are present in cortical proximal tubules. The majority of casts consist of amorphous to elongate crystalline, brightly eosinophilic material (hemoglobin casts) with fewer casts composed of eosinophilic, amorphous, globular or granular material variably admixed with sloughed epithelial cells (hyaline, cellular or granular casts). Less severely affected tubules within the cortex contain globular proteinaceous debris. When viewed with polarized light, casts contain small numbers of refractile, white, acicular, 5um x 20-30um crystals. The epithelium lining these tubules is in various stages of degeneration, necrosis, and early regeneration, characterized by cells that are markedly attenuated, hypereosinophilic with pyknotic or karyorrhectic nuclei, or sloughed into the tubular lumen (degeneration and necrosis). Some cells display anisocytosis, anisokaryosis, aggregation, hyperchromatic nuclei and occasional mitoses (regeneration). Scattered tubular epithelial cells contain brown granular cytoplasmic pigment. The tubular basement membrane is multifocally disrupted, and the adjacent interstitium is mildly edematous and has a mild interstitial infiltrate of neutrophils. Glomeruli diffusely have moderate amounts of proteinaceous material within Bowmans space. Within the vasa recta, there is variable congestion and neutrophilic leukostasis.

Morphologic Diagnosis:  

Tubular epithelial degeneration and necrosis, acute, diffuse, severe, with regeneration, and marked intratubular hemoglobin, hyaline, and granular cast formation, consistent with hemoglobinuric nephrosis, kidney, Italian greyhound breed canine

Lab Results:  

At presentation to the teaching hospital the dogs hematocrit was 5% (37-55), white blood cell count was 51.7 x103/ul (6-17) (95% neutrophils, no bands), hemolysis index 2567 (3-56), creatinine was 6.9 mg/dl (0.6-1.4), and blood urea nitrogen was 185 mg/dl (12-26). The dog was anuric, and no urine was available for diagnostic testing. A Coombs test was not performed on this patient.


Hemoglobinuric nephrosis

Contributor Comment:  

Clinical pathology data for this patient suggests an acute intravascular hemolysis, likely secondary to autoimmune mechanisms. The proximal tubular necrosis, in conjunction with the dramatic, widespread accumulation of obstructive hemoglobin casts, is consistent with peracute primary hemoglobin toxicity. Primary hemoglobin nephrotoxicity has a controversial role in veterinary medicine, although it is widely recognized in human medicine as a common and serious postoperative complication following cardiopulmonary bypass1 and, less commonly, in certain envenomations. Two diverging theories hold that hemoglobin is 1) not a direct nephrotoxin, but rather induces renal damage by a combination of hemoglobininduced hypotension, increased vascular resistance, and disseminated intravascular coagulation resulting in renal ischemia; or 2) that hemoglobin is not directly toxic, but is converted to toxic byproducts within the urinary space, thereby inducing tubular necrosis.3 In experimental studies utilizing intravenously administered purified hemoglobin in rats, Zager et. al. 3concluded that hemoglobin can act as a primary nephrotoxin only in the presence of aciduria, and that the likely mechanism for this is aciduria-dependent conversion of hemoglobin to methemoglobin, the latter of which precipitates within distal tubule segments and forms casts. Unlike hemoglobin, once methemoglobin forms its precipitation can occur under either aciduric or alkalinuric conditions, and is more toxic than hemoglobin under either condition. Furthermore, distal tubular obstruction can lead to enhanced upstream uptake of hemoglobin and its metabolites by proximal tubules.3 Tubular damage in this case likely resulted from both local and systemic contributing factors, including massive, widespread tubular obstruction and attendant tubular epithelial necrosis, hypoxia secondary to the markedly decreased hematocrit, and hemoglobin-induced vasoconstriction via activation of the renin-angiotensin and sympathetic nervous system.2 The patient had mildly to moderately elevated D-dimers and partial thromboplastin time, but normal prothrombin time and no clinical evidence of bleeding. Calculation of the lipemia, free hemoglobin, and bilirubin is performed on a clinical chemistry analyzer by passing light of different wavelengths through the serum or plasma and calculating the amount of each interfering substance based on the light absorption of the sample. The amount of free hemoglobin is reported as the hemolysis index in units of mg/dL. Elevations as high as those present in this case can falsely decrease bicarbonate, GGT, amylase, and alkaline phosphatase, and can falsely increase AST, CK, iron, phosphate, triglycerides, magnesium, and total protein.

JPC Diagnosis:  

Kidney: Tubular degeneration, necrosis, and regeneration, diffuse, marked with hemoglobin and granular casts and rare glomerular fibrin thrombi

Conference Comment:  

Acute renal failure is often caused by acute tubular necrosis. Acute tubular necrosis is usually caused by either nephrotoxic agents from the bloodstream, ischemia, or complete urinary outflow obstruction. The anatomic locations most susceptible to acute tubular necrosis are the proximal convoluted tubule and the thick ascending limb of the loop of Henle. This is in direct correlation to their high metabolic activity thus making them more susceptible to damage and necrosis.2

Ischemic tubular necrosis usually follows profound shock, and the extreme decrease in blood flow to the kidney results in renal cortical necrosis. The histologic hallmark of ischemic acute tubular necrosis is necrosis of the proximal, and to a lesser extent, distal tubules with disruption of tubular basement membranes and plugging of tubular lumina by casts. If the basement membrane is extensively damaged, then regeneration is impossible and the prognosis becomes grave.2

Nephrotoxic acute tubular necrosis causes necrosis of the proximal convoluted tubule because of the PCTs exposure to more toxin than the rest of the nephron as well as its high metabolic activity. The basement membrane is normally preserved in cases of nephrotoxic acute tubular necrosis providing scaffolding for cells to regenerate thus making the prognosis much more favorable than ischemic acute tubular necrosis.2

During the conference, several causes of tubular necrosis were discussed. Aminoglycosides, tetracyclines, sulfonamides, and the antifungal agent amphotericin B can cause tubular necrosis in domestic animals.2 Ethylene glycol is also a common cause of tubular necrosis in dogs and cats. Oxalate containing plants including Halgeton glomeratus (halogeton), Sarcobatus vermiculatas (greasewood), Rheum rhaponticum (rhubarb) are a few of the oxalate containing plants that cause poisoning in sheep and cattle.2 Other plants that cause tubular necrosis include Easter lily in cats, Quercus spp. (oak) in ruminants, and Amaranthus retroflexus (pigweed) in pigs and cattle.2Apergillus niger and flavus can also produce enough oxalates to cause renal damage when ingested with feedstuffs.2 Grapes and raisins cause tubular necrosis in dogs.2


1. Haase M, Haase-Fielitz A, Bagshaw SM, Ronco C, Bellomo R: Cardiopulmonary bypass-associated acute kidney injury: a pigment nephropathy? Contrib Nephrol 156:340-353, 2007
2. Schlafer DH, Miller, RB: Inflammatory Diseases of the Uterus. In: Jubb, Kennedy, and Palmers Pathology of Domestic Animals, ed. Maxie, MG, 5th ed., vol. 2, pp 466-469. Elsevier, Philadelphia, USA, 2007
3. Zager RA, Gamelin LM: Pathogenetic mechanisms in experimental hemoglobinuric acute renal failure. Am J Physiol 256:F446-F455, 1989

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1-1. Kidney

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