Introduction

Fanconi syndrome is characterized by reabsorptive defects of the proximal renal tubules, which can cause excessive loss of glucose, amino acids, electrolytes, bicarbonate, phosphate, and low-molecular-weight proteins into the urine.¹ Fanconi syndrome is generally inherited and chronic in nature, but there are reports of transiently acquired Fanconi syndrome in human and veterinary medicine.^2,3 An acquired Fanconi syndrome has also been documented in association with chicken jerky treats and antibiotics such as amoxicillin and gentamicin as well as in conjunction with copper storage hepatopathy in dogs.^2–6

Firocoxib is a nonsteroidal anti-inflammatory drug (NSAID) of the COX-2 inhibitor class, approved for use in dogs, and cefadroxil is a broad-spectrum antibiotic of the cephalosporin type. The patient in this report had a history of exposure to several drugs including firocoxib and cefadroxil, which are known to induce nephropathy. Here, we describe a case of transient Fanconi syndrome in a Maltese following administration of firocoxib, cefadroxil, tramadol, and famotidine.

Case Report

A 10 mo old intact male Maltese was presented to the Veterinary Teaching Hospital of Seoul National University with a 2 wk history of lethargy, anorexia, vomiting, and weight loss. The dog had undergone bilateral surgical repair of medial patellar luxation 40 days earlier. After the surgery, the dog was treated with tramadol^a (2 mg/kg orally q 12 hr for 5 days), cefadroxil^b (22 mg/kg orally q 12 hr for 7 days), famotidine^c (0.5 mg/kg orally q 12 hr for 7 days), and firocoxib^d (5 mg/kg orally q 24 hr for 26 days). Twenty-six days after the surgery, the dog showed anorexia and vomiting. The owner discontinued firocoxib 26 days after the surgery because of worsening clinical signs. The dog was presented 14 days after starting to show the signs. Hematology and biochemistry results were normal before and after the surgery (Table 1). Urinalysis showed a specific gravity of 1.043 with no evidence of glucosuria or proteinuria. There was no history of exposure to chicken jerky.

TABLE 1 Laboratory Analysis of Serial Serum and Urine Samples Obtained from a Dog with Fanconi Syndrome

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At evaluation, the dog was ∼7% dehydrated and showed dull mentation. The dog was afebrile (rectal temperature 37.4°C and had a pulse of 114 beats/min, a respiratory rate of 18 breaths/min, a weight of 0.9 kg, and a body condition score of 2/9. Systolic blood pressure (75 mm Hg) was decreased. A complete blood count was within normal limits, and serum biochemistry revealed that blood urea nitrogen and creatinine levels were normal (Table 1). Blood liver enzyme activity, albumin, and total protein were normal. His phosphorus level was marginally low, and his calcium and ionized calcium levels were decreased. Hyponatremia, hypokalemia, and hypoglycemia were documented. Urinalysis revealed isosthenuria, glucosuria, and ketonuria. Urine sediment evaluation did not reveal abnormalities, and bacteriologic culture of urine did not show bacteria. Venous acid–based analysis documented metabolic acidosis with a pH of 6.97, a venous CO₂ pressure of 39.3 mm Hg, and a bicarbonate concentration of 7.9 mg/dL. Diagnostic imaging included thoracic radiography and abdominal ultrasonography. The results of the thoracic radiography were normal, and the ultrasonographic evaluation revealed increased echogenicity of the kidneys bilaterally.

The findings of glucosuria in the absence of hyperglycemia and metabolic acidosis supported a diagnosis of Fanconi syndrome. The results of a urine metabolic profile, performed at the University of Pennsylvania, were also consistent with Fanconi syndrome, with marked glucosuria and severe generalized aminoaciduria. Serial blood gas analysis, urine dipstick tests, and electrolyte and serum glucose measurements indicated that the dog was persistently ketonuric and glucosuric with metabolic acidosis.

After admission to the intensive care unit, IV fluid therapy was instituted using a balanced electrolyte solution^e with 20 mEq/L of KCl at 5 mL/kg/hr. This solution was administered because of its comparatively high alkali content (50 mEq/L) as a result of the dog’s acidosis. The high rate of fluid administration (∼2 times the maintenance rate) was chosen to correct the severe dehydration. His respiratory and heart rates were monitored in the intensive care unit to ensure that overhydration did not occur. Sodium bicarbonate^f was administered at 3 mEq/kg/hr as a continuous rate infusion to correct the persistent metabolic acidosis. After the infusion, the venous pH increased to 7.19 and the bicarbonate concentration increased to 13.4 mEq/L. The patient received a bolus of 50% dextrose^g (1 mL/kg IV once) followed by IV fluid supplementation with 50 mL/L of 50% dextrose for hypoglycemia. The dog was also treated with famotidine^h (0.5 mg/kg IV q 12 hr) and maropitantⁱ (1 mg/kg subcutaneously q 24 hr) to control vomiting.

On day 2 of hospitalization, the dog’s appetite markedly increased, and there was no vomiting. Electrolyte analysis revealed mildly improved sodium and potassium levels, and serum glucose was within normal limits (Table 1). His venous pH was 7.22, and his bicarbonate concentration was 14 mEq/L. The metabolic acidosis was improved, so the continuous rate infusion of additional sodium bicarbonate was discontinued. Treatment and fluid therapy were continued as before.

On day 4 of hospitalization, serum biochemical analysis documented normal sodium and potassium levels (Table 1). The venous pH and bicarbonate concentration were within the reference ranges.

On day 5, the dog was removed from intensive care and serum biochemical analyses were repeated. Blood urea nitrogen, creatinine, calcium, and phosphate were normal (Table 1). The dog was discharged with the following supplements: sodium bicarbonate^j (355 mg/dose orally q 12 hr) and potassium gluconate^k (1 mEq/kg orally q 12 hr). The owner was also instructed to administer vitamin and amino acid supplements.

Two weeks after discharge, urine pH was 8 and glucosuria (4+ to 1+) was decreased. Venous pH was 7.4, and bicarbonate was 22.7 mg/dL, so the bicarbonate dosage was reduced by half. Two weeks after decreasing the oral bicarbonate supplementation, the venous pH was 7.46 and bicarbonate was 25 mg/dL, so bicarbonate supplementation was discontinued. The dog was no longer glucosuric or ketonuric. Two months after the initial diagnosis and treatment, urinalysis showed a specific gravity of 1.043 with no evidence of glucosuria or proteinuria. The results of a urine metabolic profile test at that time also revealed that there was no glucosuria or generalized aminoaciduria. The dog has been doing well with no clinical signs reported.

Discussion

This report describes transient acquired Fanconi syndrome in a Maltese with exposure to firocoxib, cefadroxil, tramadol, and famotidine. The initial presentation of the dog with glucosuria in the absence of hyperglycemia was consistent with Fanconi syndrome, which was confirmed by demonstration of severe generalized aminoaciduria.⁴ Fanconi syndrome is a rare disorder in veterinary medicine, characterized by impaired proximal tubular reabsorption of glucose, amino acids, bicarbonate, water, and other electrolytes.¹ Therefore, Fanconi syndrome is termed a “wasting disease.” A patient with Fanconi syndrome has clinical signs of polyuria, polydipsia, weight loss, and dehydration. Overall, the clinical signs and physical examination findings in the dog were nonspecific, making an early diagnosis difficult and thus delaying treatment.² This syndrome has rarely been reported in dogs and was first recognized as a congenital defect in basenjis.⁷ Acquired renal tubular defects resulting in Fanconi syndrome have been described in association with many exogenous agents, including anticancer, antibacterial, and antiviral drugs, in both humans and dogs.^5,8 Fanconi syndrome has also been associated with chicken jerky treats in dogs.^2,4 The dog in this report had no history of exposure to chicken jerky. The patient had a history of exposure to several drugs, including firocoxib, cefadroxil, tramadol, and famotidine. Based on the Naranjo probability scale, the drugs were the probable cause of Fanconi syndrome in our patient.^9,10 Because multiple drugs were involved, it was not possible to determine which was the culprit. However, the onset of signs suggested the main causal link to his latest and longest drug, firocoxib.

Firocoxib is an NSAID that is currently approved for use in dogs. To date, there is limited data concerning the role of NSAIDs as a cause of proximal tubular dysfunction in humans and dogs. However, it has been proposed that NSAIDs such as firocoxib can independently induce two different forms of kidney injury; the most common form is caused by a reduction of renal blood flow mediated by reduced prostaglandin synthesis, and the other form is caused by interstitial nephritis.^11–13 The reduction in renal prostaglandins caused by use of NSAIDs may result in renal hypoperfusion, electrolyte imbalance, and acute tubular or cortical necrosis.¹⁴ Acute interstitial nephritis is one of the main causes of tubular dysfunction.¹⁵ There are numerous causes of interstitial nephritis, mostly involving drugs, of which NSAIDs and antibiotics are the most common.^15,16 Acute interstitial nephritis can often cause tubular dysfunction, which could present with phosphaturia, bicarbonaturia, aminoaciduria, polyuria, and renal tubular acidosis. Therefore, this feature might clinically resemble acquired Fanconi syndrome.¹⁵ Although it usually occurs with excessive doses, it can occur at doses below the recommended maximum.^12,13 Renal tubulopathy has also been documented in association with NSAIDs in humans.^11,17 Fortunately, NSAID-induced renal complications are typically fully reversible if the clinician suspects such complications when presented with laboratory and histologic findings and swiftly discontinues the offending NSAID.¹²

Cefadroxil is a broad-spectrum antibiotic of the cephalosporin type. Most of the cephalosporins are not obviously nephrotoxic.¹⁸ However, production of acute proximal tubular necrosis by therapeutic doses of cephaloridine, the second drug developed in this group, has raised concern regarding the cephalosporins.¹⁹ An acquired Fanconi syndrome has also been documented in association with cephalothin and gentamicin therapy in humans.²⁰ Given that treatment with either cefadroxil or firocoxib carries a small but definite risk of nephrotoxicity, it is not surprising that the ability of these two drugs to cause renal tubular damage might be more severe when they are used in combination in susceptible patients.

Tramadol and famotidine are not obviously nephrotoxic. According to FDA reports, Fanconi syndrome is found among people who take tramadol and famotidine.^21,22 However, most of them were suffering from a disease that could cause Fanconi syndrome or taking other drugs with nephrotoxicity.^23,24 Therefore, the association between tramadol and Fanconi syndrome has not been clarified. More studies are needed to confirm this.

Severe glucosuria in the absence of hyperglycemia and aminoaciduria are hallmarks of Fanconi syndrome.²⁵ Our dog was hypoglycemic, most likely because of urinary glucose loss, prolonged anorexia, and, possibly, small body size.²⁶ Ketonuria was detected and may have been caused by anorexia-induced fat metabolism and an increased filtered load of ketones.²⁷ Other clinicopathologic findings usually include increased urinary loss of phosphate, calcium, and potassium. Impaired bicarbonate reabsorption leads to metabolic acidosis. Severe generalized aminoaciduria occurs in Fanconi syndrome because of decreased reabsorption of amino acids in the proximal renal tubules.¹ The hypophosphatemia and hypocalcemia are also consistent with increased loss of calcium and phosphorus through the urine, which is caused by Fanconi syndrome.⁷

When treating Fanconi syndrome, it is most important to identify and remove any underlying cause. Continued administration of a nephrotoxin can result in a more severe and persistent Fanconi syndrome or even fatal renal failure, whereas early immediate withdrawal limits the damage, and the syndrome can be reversed. The remainder were treated primarily with IV crystalloids and oral or IV supplements aimed at countering metabolic derangements.²⁶ The dog in this report required supportive treatment to correct the acid–base and electrolyte imbalances and other deficiencies (bicarbonate, calcium, phosphorus, amino acids, and vitamins). Correction of metabolic acidosis by parenteral or oral administration of bicarbonate is the most important treatment goal. Other treatment goals include normalizing electrolyte concentrations by providing potassium supplementation based on serum potassium levels and giving oral phosphorus and calcium supplements if a hypophosphatemia or hypocalcemia is present.⁴

One limitation of the diagnostic work-up during examination was the omission of leptospirosis titers. However, the dog lived in a single-pet household, did not frequent boarding facilities or communal parks, and was not exposed to a free-standing fresh water source. Therefore, although leptospirosis could not be definitively excluded, it was considered highly unlikely. Another limitation is that the dog in this case report did not undergo renal biopsy; therefore, a histologic prognosis could not be determined by examination of the tubular basement membrane and degree of tubular injury.

Conclusion

The disease in this dog was unique in several respects. One month after discharge, all laboratory abnormalities had resolved. Complete resolution of Fanconi syndrome was detected by re-evaluation of the urine metabolic profile. The dog remained clinically normal and did not have any recurrence of clinical signs for 2 mo after being discharged from the hospital. The unique features of Fanconi syndrome in the present case emphasize the potential renal tubular toxicity of this widely used multiple-drug combination. More studies are needed to confirm this.