Eight-year-old, female, Labrador retriever, (Canis familiaris).The dog had a history of polyuria and polydipsia with several urinary accidents. Otherwise, she was clinically healthy. Initial blood work showed azotemia (BUN: 26 mg/dL [reference range: 5-20]; serum creatinine: 2.0 mg/dL [reference range: 0.6-1.6]) and glucosuria (4+) with normal blood glucose. There was also increased ALT (458 IU/L [reference range: 10-55]). Her urine was isosthenuric and contained fine granular casts. Her blood pressure was normal (systemic blood pressure: 140 mmHg). There was no history of exposure to toxins.  Subsequent blood work one month later showed increased azotemia (BUN: 23 mg/dL; serum creatinine: 3.0 mg/dL), ALT (707 IU/L), and mild proteinuria (UPC: 1.3 [normal <0.5]).

Gross Description:  

A wedge biopsy of the renal cortex was submitted for evaluation. Wedge biopsies of liver were also harvested and submitted to a different diagnostic laboratory.  No gross abnormalities were observed at surgery.

Histopathologic Description:

(H&E): There is loss of the apical brush border of the proximal tubules. Scattered tubules are necrotic with cellular casts within lumens and attenuated or absent epithelial lining. Tubules are dilated and undergoing degeneration with single cell necrosis and apoptosis. The tubular epithelial cells contain variably sized cytoplasmic vacuoles with abundant granular pigment. There is marked epithelial cell karyomegaly. A few glomeruli have minimal to mild mesangial expansion and the interstitium is mildly expanded by fibroplasia with scattered aggregates of lymphocytes and macrophages.
Special stains: Rhodanine stain: Scattered tubular epithelial cells contain small and large red-brown granules, consistent with copper. PAS demonstrates multifocal marked loss of the apical brush borders.  The trichrome stain demonstrates a few large regions of mild to moderate interstitial fibrosis.

Morphologic Diagnosis:  

Moderate to severe tubular degeneration with necrosis, regeneration, atrophy, epithelial cell karyomegaly and scattered intracytoplasmic copper within tubular epithelial cells. Mild multifocal interstitial fibrosis.

Lab Results:  

The unfixed renal tissue that had been submitted for IF evaluation, and a portion of the liver sample were submitted to Colorado State Diagnostic Laboratory to measure copper. There was evidence of copper hepatopathy (copper 2,690 ppm [>1,500 ppm in the liver is considered toxic]) and copper in the kidney 243.00 ppm (relevant reference range >100 ppm in non-hepatic tissue being indicative of toxicity).  Urine was also submitted approximately 10 days after the biopsy.  SDS-PAGE analysis of urine demonstrated proteinuria due to the presence of low molecular weight proteins, consistent with tubular damage and absence of glomerular injury.  An aliquot of this urine sample was submitted to PennGen which documented generalized amino-aciduria and glucosuria without ketonuria or cystinuria warranting a diagnosis of acquired Fanconi syndrome.


Fanconi-like syndrome

Contributor Comment:  

The lesions presented in this case are indicative of renal proximal tubular injury, which was clinically supported by the urinalysis results.  These acquired lesions have been associated with copper storage hepatopathy as a part of Wilson’s disease in humans and dogs.  Acquired Fanconi syndrome is characterized by impaired reabsorptive function of the proximal renal tubules. Clinical features include excessive loss of water, glucose, amino acids, uric acid in the urine, and electrolyte abnormalities. The inherited form of Fanconi-like syndrome is well described in Basenji dog and is thought to be due to increased amounts of cholesterol in the tubular epithelial brush border compared to normal dogs. In contrast, acquired proximal renal tubulopathies have been loosely characterized in the literature and is attributed to many causes including copper hepatopathy, leptospirosis, hypo-parathyroidism, ethylene glycol toxicity, antibiotic, and chicken jerky treats.

In humans, Wilson’s disease is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. Decreased expression of this gene leads to decreased biliary excretion of copper resulting in hepatic copper accumulation. Patients with Wilson’s disease also accumulate copper in various tissues including the brain, eye, and kidney. Copper storage diseases have been reported in several canine breeds including Bedlington terrier, Labrador retriever, Doberman pinscher, Dalmatian, Skye terrier and West Highland white terrier. The inherited form of copper storage disease has been well documented in Bedlington terrier in which the copper metabolism domain containing 1 (COMMD1) gene is affected. The COMMD1 protein is important for copper excretion into bile during states of elevated intracellular copper. Hepatic histopathology of copper associated hepatopathies generally present with mixed inflammation (neutro-philic, lymphoplasmacytic, histiocytic) and is usually localized to the centrilobular regions. Centrilobular necrosis, bridging fibrosis, and cirrhosis have also been described in copper-associated hepatitis. Of note, chronic liver injury will lead to increased amounts of copper in the hepatocytes, sometimes making it difficult to discern whether intracellular copper is the cause or the effect of the liver injury.

A few case series/reports have documented acquired proximal renal tubulopathies associated with copper storage hepatopathy in dogs. Breeds included are: Clumber spaniel, West Highland white terrier, Cardigan Welsh corgi, and Labrador retriever.  The renal histologic findings in previous reported cases were consistent with the case presented here. Histologic evaluation of the renal tissues showed proximal tubular epithelial degeneration, necrosis, and regeneration. The tubular epithelial cells were plump with variably sized vacuoles. Using rhodanine stain, one case reported copper deposition was mainly localized to the corticomedullary junction and medullary areas; however copper staining can be variable.  Therefore, mild tubular epithelial cell degeneration and loss of the apical brush border in the setting of clinical symptoms of Fanconi syndrome should alert the pathologist to possible copper-mediated damage to the renal proximal tubules. Assay of copper levels in the liver or kidney samples supports this pathogenesis.

In previous case reports of copper hepatopathy induced proximal renal tubular disease, there was improvement and resolution of clinical signs with copper chelation therapy, specifically using d-penicillamine. Additional therapies including supportive care, antioxidants, and low copper diet can also contribute to improvement of clinical signs.

JPC Diagnosis:  

Kidney, tubules: Epithelial degeneration, re-generation, and necrosis, diffuse, marked, with karyomegaly, few tubular casts, intracytoplasmic pigment and interstitial fibrosis, Labrador retriever, Canis familiaris.

Conference Comment:  

The contributor provides an excellent example and thorough review of copper-associated acquired Fanconi-like syndrome. This syndrome is characterized by polyuria, polydipsia, hyposthenuria, glucosuria with normo-glycemia, hyperphosphaturia, proteinuria, and amino aciduria due to impaired renal tubular absorption of glucose, phosphates, sodium, potassium, uric acid, and amino acids.1,2,4,7 In this case, this animal had glucosuria with normoglycemia and amino-aciduria indicating poor proximal convoluted tubular functioning. Glucose is normally resorbed in the renal proximal tubules via the sodium-glucose co-transport system.1,7,9 The concentration gradient established by this system also promotes sodium resorption from the tubular fluid. In congenital or acquired tubular defects of Fanconi-like syndrome, glucose is not resorbed and will cause an osmotic diuresis. This diuresis causes a marked decrease in kidney’s ability to concentrate urine and will increase urine volume; indicated by polyuria and isosthenuria reported in this case.1,7,9 The polydipsia is likely secondary to compensation from increased fluid loss in the urine.

Conference participants discussed the significance of the reported presence of low molecular weight proteins in the urine using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). In general, there are four main types of proteinuria: pre-renal, glomerular, tubular, and hemorrhagic/inflammatory. In pre-renal proteinuria, small proteins such as hemoglobin dimers, myoglobin, and light chains are present in the plasma at increased concentrations and pass through the glomerulus and are incompletely resorbed by fully functioning tubules.8 Glomerular proteinuria is characterized by damage to the glomerulus, thus enabling high molecular weight and negatively charged proteins to leak into the filtrate and pass into the urine due to loss of selective permeability.8 In tubular proteinuria, proximal renal tubules are damaged or defective so low molecular weight proteins, like smaller globulins and some albumen, do not get resorbed from the ultra-filtrate and are excreted in the urine. Hemorrhagic/inflammatory proteinuria occurs due to hemorrhage or inflammation within the renal tubules, renal pelvis, or lower urinary tract. In this case, SDS-PAGE detected low molecular weight proteins within the urine and suggests that the primary lesion is in the proximal tubules rather than the glomeruli.8 This finding is confirmed by the histopathology of the kidney in this case. The characterization of proteinuria by SDS-PAGE is a useful antemortem clinical tool to identify the main pathophysiologic mechanism involved.

Although not reported in this case, this animal was likely in a secretory metabolic acidosis due to renal tubular acidosis and loss of bicarbonate through the urine. In cases of Fanconi-like syndrome, the renal proximal tubules fail to resorb filtered bicarbonate.3 Other causes of secretory metabolic acidosis include vomiting of intestinal contents rich in bicarbonate, diarrhea, and an inability to swallow saliva rich in bicarbonate in ruminants during dysphagia.3 The hallmark of this type of acidosis is concurrent hyperchloremia as the body attempts to maintain electroneutrality. In addition, the anion gap will typically be normal because unmeasured anions are not increased.3


1. Appleman EH, Cianciolo R, Mosenco AS, Bounds ME, et al. Transient Acquired Fanconi Syndrome Associated with Copper Storage Hepatopathy in 3 Dogs. J Vet Intern Med. 2008; 22:1038-1042.
2. Coronado VA, O’Neill B,Nanji M, Cox DW. Polymorphisms in canine ATP7B: candidate modifier of copper toxicosis in the Bedlington terrier. Vet J. 2008; 2:293-96.
3. George JW, Zabolotsky SM. Water, electrolytes, and acid base. In: Latimer KS, ed. Duncan and Prasse’s Veterinary Laboratory Medicine Clinical Pathology. 5th ed. Ames, IA: Iowa State University Press; 2011:163-166.
4. Hill TL, Breitschwerdt EB, Cecere T, Vaden S. Concurrent Hepatic Copper Toxicosis and Fanconi’s Syndrome in a Dog. J Vet Intern Med. 2008; 22:219–22.
5. Hoffman G. Copper-Associated Liver Diseases. Vet Clin Small Anim. 2009; 39:489–511.
6. Hooper AN, Roberts BK. Fanconi syndrome in four non-basenji dogs exposed to chicken jerky treats. J Am Anim Hosp Assoc. 2011; 47:e178-87.
7. Langlois DK, Smedley RC, Schall WD, Kruger JM. Acquired proximal renal tubular dysfunction in 9 Labrador retrievers with copper-associated hepatitis (2006-2012). J Vet Intern Med. 2013; 27:491-9.
8. Stockham SL, Scott MA. Urinary system. In: Fundamentals of Veterinary Clinical Pathology. 2nd ed. Ames, IA: Blackwell Publishing; 2008:458-460.
9. Thompson MF, Fleeman LM, Kessell AE, Steenhard LA, Foster SF. Acquired proximal renal tubulopathy in dogs exposed to a common dried chicken treat: retrospective study of 108 cases (2007-2009). 2013. Aust Vet J. 9;368-73.

Click the slide to view.

3-1. Kidney, dog.

3-2. Kidney, dog.

3-3. Kidney, dog.

3-4. Kidney, dog.

3-5. Kidney, dog.

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