Conference 24 - 2012 Case: 01 20130508

Signalment:

Three-month-old, female domestic shorthair cat (Felis cats).The kitten came from a breeding colony at the College of Veterinary Medicine, Cornell University.

Gross Description:

The kidneys are bilaterally enlarged; each measures approximately 4 x 3 x 2.5 cm. On section, the parenchyma exudes a small amount of clear fluid. Dozens of pinpoint to linear white foci are scattered throughout the cortex and medulla (tubular crystalluria).

Histopathologic Description:

Kidney (1 section): Frequent tubules within the cortex and, to a lesser extent, the medulla, are occluded by linear crystalline material arranged into radiating sheaths. Crystals are translucent, clear to blue and birefringent bright white under polarized light (oxalate crystals). Cortical tubules are irregularly ectatic and variably lined by flattened, attenuated epithelium with hypereosinophilic cytoplasm and pyknotic nuclei (degeneration and necrosis) or, rarely, by plump, basophilic cells that are haphazardly stacked (regeneration). Scattered tubules additionally contain karyorrhectic debris and droplets of homogenous, eosinophilic material (protein). Small numbers of lymphocytes, plasma cells and neutrophils multifocally infiltrate the cortical and medullary interstitium and fine threads of fibroblasts occasionally dissect between tubules (fibrosis).

Morphologic Diagnosis:

1. Kidney: Moderate, diffuse, subacute tubular necrosis and ectasia with multifocal tubular epithelial regeneration and many intratubular oxalate crystals.
2. Mild, multifocal lymphoplasmacytic and neutrophilic interstitial nephritis.

Condition:

Feline primary hyperoxaluria

Contributor Comment:

This kitten was bred as a feline model of primary hyperoxaluria; the histologic features of the examined section of kidney are characteristic of this disease. Primary hyperoxaluria (PH) is best described in humans but has also been reported in cats, dogs and cattle.(2,3,4,5) In humans PH is a rare, autosomal recessive inherited disease that is classified as either type I (PH1) or type II (PH2) based on mutations of the respective genes alanine: glyoxylate aminotransferase (AGT) and glyoxylate reductase/ hydroxypyruvate reductase (GRHPR), and their associated biochemical deficits. Up to 83 AGT mutations have been associated with PH1 and 13 mutations of GRHPR have been identified in cases of PH2; these mutations reduce or eliminate activity of the hepatic enzymes AGT and GRHPR.1 Consequently, increased glyoxalate and hydroxypyruvate are available for conversion by lactate dehydrogenase to oxalate and, in the case of PH2, L-glyceric acid. The resultant errors in glyoxylate metabolism lead to markedly increased serum and urinary oxalate concentrations. Patients with PH2 also have L-glyceric aciduria as GRHPR mutations disrupt the hydroxypyruvate reductase pathway leading to production of L-glycerate in hepatocyte cytoplasm.(2,6) Mammals cannot metabolize oxalate, which is primarily excreted through the kidneys. In PH, oxalate binds with free calcium ions forming insoluble crystals; once the urine is super-saturated calcium oxalate crystals are deposited in renal tubules and, to a lesser extent, the renal interstitium. As renal excretion of oxalate declines, systemic deposition of calcium oxalate occurs and the retina, myocardium, central nervous system, skin, bone and blood vessel walls may be involved. Clinical disease in humans manifests by recurrent oxalate urolithiasis and nephrocalcinosis leading to end-stage renal failure and death, if untreated. Diagnosis is usually made when disease is already advanced; patients require dialysis and combined kidney and liver transplantation.(6)

A naturally occurring disease in cats, clinically similar to PH2 in humans, has been described in several instances.(2,3,4) As with humans, the disease is autosomal recessive and typically affects kittens between five and nine months of age. Affected animals develop acute renal failure with increased urinary oxalate and L-glyceric acid levels. Histologically, abundant oxalate crystals are present within renal tubules and occasionally Bowmans spaces, accompanied by acute tubular necrosis and, variably, mild interstitial fibrosis.(3) Also consistent with human PH2, GRHPR mutation has been associated with the feline disease in cats from one colony.(4) A point mutation in the acceptor site of intron 4 was identified and correlated with a frameshift and premature stop codon in RNA transcripts from affected cats.

Several distinct differences exist in the clinical presentation of feline primary hyperoxaluria and PH2 in humans. Human PH2 is typically diagnosed in adults when renal changes are chronic; stone formation is usually less severe than that observed in PH1, which may present in infancy. By contrast, feline PH presents in young animals and is characterized by severe, acute disease. Concurrent neurologic lesions may accompany renal disease in cats and are histologically typified by swelling in the proximal axons of spinal motor neurons, ventral roots and intramuscular nerves and the dorsal root ganglia due to neurofilamentous accumulations. This lesion may be accompanied by Wallerian degeneration in peripheral nerves and associated denervation muscle atrophy. It is uncertain how these changes relate to the metabolic deficits present in primary hyperoxaluria or whether they represent a concurrent genetic defect.(3,7)

Primary hyperoxaluria must be distinguished from secondary disease due to exposure to large amounts of oxalates or increased absorption of dietary oxalic acid from the intestinal tract. In companion animals, acute oxalate nephrosis is typically seen in cases of ethylene glycol poisoning. In large animals, oxalate-rich plants are generally the source of toxicity.(8) Histologically, renal changes due to ethylene glycol toxicity are indiscernible from those present in cases of feline primary hyperoxaluria. A distinction between feline primary hyperoxaluria and oxalate toxicity is made on the basis of clinical history and supporting clinicopathological information (e.g. L-glyceric aciduria).

JPC Diagnosis:

1. Kidney: Tubular degeneration and necrosis, diffuse, marked, with regeneration, mineralization, and numerous intratubular oxalate crystals.
2. Kidney: Nephritis, interstitial, lymphoplasmacytic, multifocal to coalescing, mild, with fibrosis.

Conference Comment:

The contributor provides an excellent synopsis of primary hyperoxaluria (PH). Given only the species of origin in advance of the conference, participants correctly determined that this was a young animal based on the occasional presence of hypercellular fetal glomeruli in the section. While most participants included PH in their differential diagnoses, ethylene glycol toxicosis was considered the most likely etiology. In addition to reviewing the pathogenesis of PH, conference participants discussed the pathogenesis of ethylene glycol toxicosis in depth. The main focus of the discussion was the clinicopathologic aberrations typical of ethylene glycol toxicosis, including titrational metabolic acidosis, hyperkalemia, hyperphosphatemia, hypocalcemia, and calcium oxalate monohydrate crystalluria.(9) A detailed review of ethylene glycol toxicosis and its associated clinicopathologic consequences is available elsewhere in these proceedings (i.e., Conference 18, Case III).

Finally, participants discussed toxic plants as the usual cause of oxalate nephrosis in ruminants. A partial listing of oxalate-containing plants implicated in such cases follows:(8)

Scientific Name	Common Name
Halogeton glomeratus	Halogeton
Sarcobatus vermiculatus	Greasewood
Rheum rhaponticum	Rhubarb
Oxalis cernua	Soursob
Rumex spp.	Sorrel, dock

References:

1. Bobrowski AE, Langman CB. The primary hyperoxalurias. Semin Nephrol. 208;28:152-162.
2. Danpure CJ, Jennings PR, Mistry J, Chalmers RA, McKerrell RE, Blakemore WF, et al. Enzymological characterization of a feline analogue of primary hyperoxaluria type 2: a model for the human disease. J Inherit Metab Dis. 1989;12:403-14.
3. De Lorenzi D, Bernardini M, Pumarola M. Primary hyperoxaluria (L-glyceric aciduria) in a cat. J Feline Med Surg. 2005;7:357-361.
4. Goldstein RE, Narala S, Sabet N, Goldstein O, McDonough SP. Primary hyperoxaluria in cats is caused by a mutation in the feline GRHPR gene. J Heredity. 2009;100:S2-S7.
5. G+â-+lbahar MY, Kaya A, G+â-¦len I. Renal Oxalosis in a Calf. Turk J Vet Anim Sci. 2002;26:1197-1200.
6. Hoppe B, Beck BB, Miller DS. The primary hyperoxalurias. Kidney Int. 2009;75:1264-1271.
7. Maxie MG, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. 5th ed. Philadelphia, PA: Elsevier Saunders; 2007:375.
8. Maxie MG, Newman SJ. Urinary system. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. 5th ed. Philadelphia, PA: Elsevier Saunders; 2007:468-473.
9. George JW, Zabolotzky SM. Water, electrolytes, and acid base. In: Latimer KS, ed. Duncan & Prasses Veterinary Laboratory Medicine Clinical Pathology. 5th ed. Ames, Iowa: Wiley-Blackwell; 2011:145-171, 430-432.