Introduction

Fanconi syndrome is a renal tubular disorder, resulting in the impaired resorption of various solutes including glucose, bicarbonate, electrolytes, amino acids, protein, and uric acid.^1,2 In humans, the syndrome can occur as an inherited condition (idiopathic or secondary to metabolic defects, e.g., cystinosis), or acquired secondary to a toxic or metabolic insult.¹ The most common canine etiology is the idiopathic inherited syndrome in basenjis, by which up to 10% of the breed in the United States may be affected.³ Acquired disease in dogs has been documented secondary to gentamicin therapy, primary hypoparathyroidism, ethylene glycol toxicity, presumed pyelonephritis, copper storage hepatopathy, and presumed toxin ingestion in dried chicken treats.^4–9

Almost all cases of Fanconi syndrome in dogs have been documented in adult animals; there are only three reports of juvenile dogs with the condition.^7,10,11 Only one previous paper reports Fanconi syndrome in canine siblings in two male border terrier littermates.¹¹ This report describes Fanconi syndrome in Irish wolfhound siblings.

Case Histories

Dog 1, an 8 mo old 50.8 kg intact male Irish wolfhound, presented to the Royal (Dick) School of Veterinary Studies, The University of Edinburgh, with a 3-mo history of polydipsia (400 mL/kg/day) and polyuria. Previous history had been unremarkable except for distichiasis, which was surgically corrected at 14 wk old. Postoperative treatment was amoxycillin/clavulanate^a and meloxicam^b. Treatment with enrofloxacin immediately prior to referral for 2 wk had not resulted in improvement.

Clinical examination was unremarkable except for tacky mucous membranes.

Complete blood count and serum biochemistry revealed polycythaemia, hyperalbuminemia, and increased creatinine (Table 1). Increased alkaline phosphatase activity was considered to be a result of ongoing bone growth. Serum glucose concentration was within the reference range. Isosthenuria, glucosuria, hematuria, and significant proteinuria were detected on urinalysis obtained by cystocentesis. Urine culture was negative (Table 2). A marked generalized aminoaciduria was documented (Table 3).

TABLE 1 Hematology and Serum Biochemistry

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TABLE 2 Urinalysis at Diagnosis

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TABLE 3 Urine Amino Acid Concentrations

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Abdominal ultrasonography showed bilateral renal changes, which included pyelectasia, cortical hyperechogenicity, and markedly hyperechoic corticomedullary junction (Figures 1A, B). The ureters were not dilated and inserted into bladder trigone normally. Venous blood gas analysis revealed a mild metabolic acidosis with inadequate respiratory compensation (Table 4). Systolic blood pressure was normal at 154 mm Hg.

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TABLE 4 Venous Blood Gas Analysis

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These findings were consistent with a diagnosis of Fanconi syndrome. Treatment was initiated using a modification of a supplementation regimen^c including sodium bicarbonate^d 53 mg/kg per os (PO) q 12 hr, daily vitamin B complex and twice-weekly amino acid^e and multivitamin/mineral supplementation^f. Despite an elevated serum creatinine suggesting potential renal dysfunction, a low-protein diet was not used because of concerns that protein levels would not be suitable for a growing dog and that reduced phosphate could lead to bone growth abnormalities or osteopenia in an acidemic dog. The dog was fed commercial puppy food. A 4-wk course of amoxycillin/clavulanate 12.5 mg/kg PO q 12 hr was also administered because chronic pyelonephritis could not be excluded.

Treatment was adjusted based on follow-up blood gas analysis and serum biochemistry. Benazepril^g 0.25 mg/kg PO q 24 hr, potassium gluconate^h 3 g PO q 12 hr, and phenylpropanolamine hydrochlorideⁱ 1 mg/kg PO q 8 hr were subsequently added because of worsening proteinuria (urine protein:creatinine ratio 4.25 with an inactive urine sediment), hypokalaemia, and urinary incontinence, respectively. Calcium 800 mg, phosphorus 154 mg, and vitamin D 5 μg^j PO q 12 hr supplementation was introduced. Partial control of incontinence and stable level of proteinuria (urine protein:creatinine ratio 3.62) were achieved. Three urinary tract infections with Escherichia coli were documented over the proceeding 8 mo, which responded to amoxycillin/clavulanate 12.5 mg/kg PO q 12 hr. Systolic blood pressure remained between 150 and 160 mm Hg at each reassessment. Overall, when metabolic acidosis and hypokalemia were controlled, demeanor and appetite were good.

Ten months post diagnosis, reluctance to exercise and thoracolumbar spinal pain were evident. Generalized osteopenia was noted on spinal radiography. Additional sodium phosphate supplementation^k 1,936 mg PO q 12 hr was commenced. The patient was euthanized at 22 mo old following a fall and suspected spinal fracture. By the time of death, supplementation doses were increased to sodium bicarbonate 174 mg/kg PO q 12 hr, benazepril 0.5 mg/kg PO q 12 hr, and daily amino acid supplementation. Both kidneys were fixed in 10% neutral buffered formalin and underwent route processing with 5-µm sections stained with hematoxylin and eosin. On histological examination, there was tubular dilation and atrophy, glomerular hypercellularity, glomerulocystic atrophy and glomerular sclerosis with interstitial inflammation (predominantly lymphocytes with fewer macrophages and plasma cells), interstitial fibrosis, and scattered foci of calcification (Figures 2A, B).

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Dog 2, a 14 mo old intact male litter sibling of dog 1, was presented to the Royal (Dick) School of Veterinary Studies, The University of Edinburgh, for evaluation of previously diagnosed Fanconi syndrome based on glucosuria, euglycemia, and generalized aminoaciduria (Table 3). The dog had been polydipsic (>220 mL/kg/day) since he came into the owner’s possession at 5 mo of age. Previous history included surgery for entropion at 14 wk old with perioperative treatment of amoxycillin/clavulanate and meloxicam.

Apart from tacky mucous membranes and suboptimal muscling, clinical examination was unremarkable.

Complete blood count and serum biochemistry revealed polycythemia, hyperalbuminemia, hyperchloremia, hypokalemia, and increased creatinine (Table 1). Glucosuria and hematuria were present but significant proteinuria was not a feature (Table 2). A marked generalized aminoaciduria was present (Table 3). Metabolic acidosis was noted on venous blood gas analysis (Table 4). Renal ultrasonographic changes were similar to dog 1, except that the hyperechoic band at the corticomedullary junction was less apparent (Figures 1C, D).

Treatment recommendations included free access to water, commercial juvenile dog food, sodium bicarbonate 67 mg/kg PO q 12 hr, potassium gluconate 2.6 g PO q 12 hr, multivitamin/mineral supplement^l one tablet PO q 48 hr, and amino acid supplementation^d two tablets PO q 24 hr.

Sodium bicarbonate doses were not adjusted because the dog was not re-presented for blood gas analysis. Urinary incontinence developed by day 90, which did not improve when the concurrent urinary tract infection due to Staphylococcus sp. was treated with amoxycillin/clavulanate 12.5 mg PO q 12 hr. Treatment was not otherwise adjusted until euthanasia at 2 yr 10 mo of age due to weight loss, diarrhea, and a change in the owners’ personal circumstances. No postmortem examination was performed.

Dog 3, a 14 mo old male sibling of dogs 1 and 2, was presented to a private veterinary practice for polydipsia, polyuria, poor weight gain, and urinary incontinence. There had been no previous health problems or prior treatment.

Diagnostic testing revealed glucosuria, euglycemia, hypokalemia, isosthenuria, and generalized aminoaciduria (Tables 1, 2, 3). Ketonuria was present initially but not detected on subsequent samples. A concurrent urinary tract infection with E coli was also detected, which was treated with amoxycillin/clavulanate 12.5 mg/kg PO q 12 hr for 2 wk.

Treatment with phenylpropanolamine 1 mg/kg PO q 8 hr resulted in improvement, but not resolution, of incontinence. Following discussion with the Royal (Dick) School of Veterinary Studies, a supplementation regimen was commenced, including a commercial juvenile life-stage diet, sodium bicarbonate 15 mg/kg PO q 12 hr, potassium gluconate supplementation 468 mg PO q 12 hr, amino acid supplementation^d, and a multivitamin/mineral supplement^m two tablets PO q 24 hr. Unfortunately, the dog was lost to follow-up until euthanasia due to acute respiratory distress at 2 yr 8 mo old. No postmortem examination was performed.

Discussion

Fanconi syndrome is a rare disease of dogs, most commonly seen as an inherited, tardive proximal renal tubular dysfunction in adult basenjis, with a typical age of onset between 3 and 8 yr old.³ Sporadic reports exist of several other breeds being affected.^4,7,9–16 There are no previous reports of Fanconi syndrome in Irish wolfhounds.

In humans, histologic changes in Fanconi syndrome are generally nonspecific or absent except in cystinosis.¹ In canine idiopathic Fanconi syndrome, histopathology may show tubular cell karyomegaly, but is otherwise normal or nonspecific.¹⁷ In these wolfhounds, the presence of ultrasonographic and histologic changes suggests that the Fanconi syndrome may be secondary to structural renal disease. Fanconi syndrome has been documented in male border terrier puppies secondary to renal dysplasia.¹¹ Although numerous structural changes were noted on renal histopathology from dog 1, these were not consistent with the criteria necessary for a diagnosis of renal dysplasia.¹⁸ A diffuse bilateral nephropathy has been previously recorded in a juvenile Irish wolfhound, but was associated with renal failure rather than Fanconi syndrome.¹⁹ It is unclear whether the histopathological changes observed were because of an abnormality in renal development or were secondary to toxic or infectious damage. The presence of disease in three littermates indicates either a common insult during gestation/early postpartum life or a genetic defect. The fact that all male dogs in the litter were affected and the females appeared to be spared suggests a possible sex-linked genetic defect. However, because the condition has not been reported in any ancestors of these dogs, whether this truly represents a hereditary nephropathy is unknown. Also, although the female siblings were reported to be unaffected and did not display overt polyuria and polydipsia, they were not presented for examination or diagnostic testing, so it could not be verified that they were clinically normal.

The exact renal defect in Fanconi syndrome is still poorly understood.¹ Therefore, therapy is focused on the management of metabolic acidosis and the replacement of lost solutes. Although the protocol used has not been tested against other treatments, in one study in which 95% of patients were being treating according to its recommendations, the mean survival times (5.25 yr) and median estimated lifespan (11.3–12.1 yr) approached those of unaffected basenjis.¹⁶ In prior reports, in basenji dogs not being treated with this regimen, 57% died within 5 mo of diagnosis.¹⁶ Although follow-up was not complete in all three dogs, morbidity (at least in dog 1) appeared to be a consequence of acidosis and metabolic bone disease rather than renal failure, which are recognized complications of human Fanconi syndrome.^1,20 Limb deformities were not seen in any of our cases, presumably because of the absence of absolute hypophosphatemia, unlike the border terrier siblings.¹¹ However, osteomalacia and a progressive decrease in serum phosphate despite supplementation were observed in dog 1. We considered a commercial diet developed for the management of renal disease, with decreased phosphate and protein as recommended for azotemic adult basenjis in the “Renal Failure Hybrid” of the Gonto protocol, as inappropriate in these dogs because they were growing and had poor muscling, and we were concerned that hypophosphatemia could lead to bone malformation or osteopenia. Using a protocol developed for adult basenji dogs in young giant breed dogs is likely to be imperfect and require modification. Therefore, refinement of treatment with more aggressive control of metabolic acidosis and phosphate, calcium, and vitamin D3 supplementation may improve the health and longevity of juvenile wolfhounds with Fanconi syndrome. Investigation of the diagnostic findings and genomics in a larger population of affected dogs and their relatives could also further understanding of this disease. However, an adult dog drinking 20 L of water daily, with concurrent urinary incontinence, represents a significant management problem and may limit owner tolerance of this condition.

Conclusion

In summary, this is the first report of Fanconi syndrome in Irish wolfhound littermates and may represent a new or previously undocumented familial nephropathy in this breed. Unlike the previous report in border terrier siblings, limb deformity was not a feature of the disease. Recognition of this disease in other individuals should stimulate the refinement of treatment and breeding strategies to reduce morbidity and incidence.