INTRODUCTION

The Fanconi syndrome is due to a constellation of renal tubular transport defects. The syndrome in the Basenji breed is a hereditary disease with varied clinical presentations peculiar to this breed. Severity of the disease is highly variable from asymptotic cases to those with renal failure, renal tubular acidosis and a fatal renal papillary necrosis. The syndrome is found in l6% of all Basenji dogs screened in North America. This syndrome was first described in humans 65 years ago; the canine disease is slightly different from the human form in that dogs do not have gastrointestinal transport defects. The diagnosis and treatment are quite difficult and are completely different from other forms of renal disease in dogs.

CLINICAL PRESENTATION

Presentation will depend on the severity of disease which is determined by the number and severity of renal tubular transport defects. Severely affected dogs will have profound polydypsia and polyuria, dehydration, weight loss, glycosuria and azotemia. Many of these dogs will progress to renal failure with acidosis and papillary necrosis over a period of months. This form on chronic renal failure is peculiar to this disease and is not successfully treated. A moderate form of the syndrome is characterized by moderate polyuria, glycosuria, gradual weight loss over years, and mild azotemia in some cases. Some of these dogs will progress slowly to the severe form and others will remain unchanged and live a normal life span. The third form is characterized by mild polyuria only or will be completely asymptomatic and avoid detection unless special testing is performed. Such testing is done when there is a related positive dog. The age at time of presentation ranges from young adulthood to 9 years; mean age for females 7 years, mean age for males 4.2 years. The sex distribution is slightly higher for females, 56% of cases.

DIAGNOSIS

The diagnosis in severe cases is based on laboratory results of this peculiar form of renal failure including moderate azotemia, glycosuria, dilute urine, and hypokalemia and hyperphosphatemia in some cases. Acidosis may be present with a low blood arterial ph and a low plasma bicarbonate suggesting renal tubular acidosis. The presence of aminoaciduria, particularly cystine, makes the diagnosis more certain. A clinical diagnosis in moderate cases is more difficult with only dilute urine, glycosuria and possible azotemia and weight loss. Since azotemia is not always present more specific tests are required.

The test we have found most helpful to identify moderate or mild cases is paper chromatography to detect aminoaciduria. Affected dogs will have excessive amino acids in the urine, notably cystine, lysine, glycine, alanine and methionine. These urine specimens may also detect sugars and organic acids commonly present in the urine. After studying hundreds of dogs and following their progression we have found that cystine is usually the first to appear in the urine and the most consistent and prominent amino acid found. It may also be detected by the chemical nitroprusside test on urine. We have tested over 1000 Basenji over a 20 year period using chromatography and have found a prevalence of l5.7% in dogs in North America. There appears to be an aging factor in this disease as immature and young adults rarely have the tubular defects but these defects appear in mid aged dogs. The screening program to detect early or minor defect cases encountered test results that were inconclusive and suspicious in about l3% of tests. These tests were repeated at yearly intervals to determine patterns of change. A small percentage of suspicious aminoaciduria findings became positive, more than half of suspicious findings became negative and 27% remained suspicious for years. Subsequent renal clearance studies to quantify aminoaciduria revealed that this breed has a population of dogs with mild aminoaciduria that do not progress to the Fanconi syndrome. A determination of positive screening tests was based on aminoaciduria alone in 40% of cases, aminoaciduria and glucose in 50%, and glucose alone in l0% of dogs.

CHARACTER OF TUBULAR DEFECTS

A more specific and quantitative test to confirm the diagnosis and determine the scope of renal tubular defects is the renal clearance of multiple solutes. Renal clearances for creatinine (glomerular filtration rate), glucose, sodium, potassium, chloride, inorganic phosphate, calcium, uric acid and amino acids were performed. The fractional reabsorption of glucose, sodium, phosphate and potassium was dramatically reduced in all severe cases and slightly reduced in moderate cases. Potassium loss was greater than the filtered load of potassium indicating tubular secretion or efflux. Chloride and calcium were seldom abnormal. Severe cases had a generalized aminoaciduria while moderate cases had variable or slight amino acid defects. These results confirmed the screening tests indicating that the earliest and most severe aminoaciduria involved cystine. Defective uric acid reabsorption is present in most dogs.

Acid-base status was studied in severe and moderately affected dogs using standard blood gas measures and the renal clearance of bicarbonate. Most severely affected dogs had acidosis out of proportion to reduction in renal function. Since most dogs with routine chronic renal failure do not develop acidosis, we investigated the possible presence of renal tubular acidosis. Bicarbonate reabsorption was decreased l0-50% compared to normal Basenji dogs. Bicarbonate infusion studies confirmed the presence of a reduced Tm for bicarbonate reabsorption. To determine if this breed is different from others in ability to conserve bicarbonate when renal mass is reduced, a 50% nephrectomy was performed on normal Basenji dogs to reduce glomerular filtration rate to levels seen in the affected Basenji. Results indicate that normal Basenji dogs are the same as other breeds confirming the presence of a specific tubular defect for bicarbonate.

Histopathology of the kidneys and specifically the tubules was unremarkable until the late stages in the severe cases. Tubulo-interstitial fibrosis was common in these dogs. When dogs developed severe acidosis and began losing weight they quickly developed renal papillary necrosis and failure. Histopathology revealed calcification of the renal papilla and acute pyelonephritis.

PATTERN OF INHERITANCE

Examination of pedigrees of affected dogs provided by breeders was not revealing since many dogs were not fully studied and some dogs developed tubular defects late in life. We were given a group of affected and suspicious dogs for breeding studies. We bred these well defined dogs to produce 8 litters with 40 offspring. Our objective was to determine when in life these defects appeared and how they progressed over time. All offspring were screened and given renal clearance studies annually. We maintained 27 of these offspring for nine years. The earliest abnormalities were minor defects in the reabsorption of sodium, inorganic phosphate, glucose and amino acids. The mating of positives to normals produced all normal offspring. Mating of positives to normals with a positive parent produced positive offspring in l0% of cases. Mating positives to chronically suspicious dogs with slight aminoaciduria produced one positive and many suspicious dogs that remained asymptomatic. Mating of positives to each other produced one litter of 4 pups which tested normal until 2.5 years of age. Three of these then developed minor defects for glucose and one had a minor defect for sodium. None developed aminoaciduria and all remained asymptomatic for nine years. Histopathology at necropsy was unremarkable. The pattern of genetic transmission remains elusive but is most consistent with an autosomal recessive pattern.

TREATMENT

A uniform protocol to treat these dogs is difficult since they change over time and most remain stable without treatment. The renal tubular acidosis can be managed at least temporarily with bicarbonate supplements but many dogs fail as the tubular defects worsen when renal tubular acidosis is present. Some have suggested oral electrolyte supplements but these have not been used in dogs with renal clearance studies to confirm the presence or severity of the defects.

CONCLUSION

This is a unique disease in regard to progression, diagnosis, and varied clinical presentation. Screening of urine using paper chromatography and then followed by renal clearance studies is required to make the diagnosis. Routine laboratory testing for renal failure is not adequate and will fail to detect tubular defects. The presence of glycosuria and cystinuria are suggestive of a positive diagnosis. Treatment of the renal tubular acidosis may be helpful in some cases, but unless acidosis is present most dogs remain stable for years without treatment of any kind. The pattern of genetic transmission is unclear. Finally, the prevalence outside of North America is unknown.

References

1.  Bovee, KC, Joyce T, Reynolds R et al. Spontaneous Fanconi syndrome in the dog. Metabolism 27:45-52, l978

2.  Easley, JR, Breitschwerdt EB. Glucosuria associated with renal tubular dysfunction in three Basenji dogs. J Am Vet Med Assoc l68:938-943, l976

3.  Bovee, KC et al. Characterization of renal defects in dogs with a syndrome similar to the Fanconi syndrome in man. J Am Vet Med Assoc l74:l094-l099, l979