Fanconi’s Syndrome in Dogs

Michael A. Davis, DVM; Perry J. Bain, DVM, PhD, Kenneth S. Latimer, DVM, PhD, and Bruce E. LeRoy, DVM, PhD.

Class of 2004 (Davis) and Department of Pathology (Bain, Latimer, LeRoy), College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7388

Fanconi’s Syndrome in Dogs

Fanconi's syndrome is an inherited disease that affects the proximal renal tubule and causes abnormalities in sodium, glucose, calcium, phosphate and amino acid retention, sometimes leading to fatal disturbances in acid-base balance.^1,2,3 The disease can also be mimicked by certain toxins and drugs that affect the proximal renal tubule and interrupt normal functioning.^4,5

Epidemiology

Fanconi's syndrome appears to have a hereditary predisposition for Basenjis as well as Norwegian Elkhounds. Other breeds that are predisposed (to a lesser degree) are Shetland sheepdogs and Schnauzers. The onset of the disease is not until later in life (3-11 yrs of age in Basenjis), and thus affected dogs may have been bred before diagnosis, passing on the genetic trait.⁶ Approximately 10% of adult Basenjis have Fanconi’s syndrome.⁶ The acquired form of Fanconi’s syndrome can be caused by heavy metal poisoning (lead, mercury, cadmium and uranium). Drugs such as a gentamicin,⁵ cephalosporins, outdated tetracycline, cisplatin, and streptozotocin can cause proximal renal tubule resorption abnormalities.⁴ Chemicals such as Lysol^® and maleic acid also have been reported to cause the syndrome.⁴ Renal cystic disease and neoplasia,³ including multiple myeloma and monoclonal gammopathies, also have been found to cause acquired Fanconi’s syndrome.⁴

Etiology

The proximal renal tubule normally resorbs 100% of the glucose that is filtered through the glomerulus in normoglycemic conditions. Glucose resorption is coupled to sodium co-transport. Glucose enters the cell under secondary active transport driven by the sodium concentration gradient. This concentration gradient between extracellular fluid and intracellular fluid is maintained by sodium-potassium ATPase on the basolateral surface of the cell which pumps sodium out of the cell and into the interstitium. There are also similar co-transports between sodium and amino acids, inorganic phosphorous, and calcium. A sodium/hydrogen ion antiporter is present in the proximal renal tubule which shuttles sodium into the cell and hydrogen into the lumen of the tubule. This antiporter is also dependent upon the concentration gradient established by the sodium-potassium pump (Fig. 1).⁷

The defect in the proximal renal tubule is not known and may vary between the inherited and acquired forms of the syndrome. There are three proposed mechanisms for the failure to re-absorb the normal amount of solutes in Fanconi’s syndrome. The first is a defect in all of the transport systems which prevents them from working effectively (Fig 2).⁴ The second proposed mechanism is a defect in the metabolism of the cell that decreases the amount of available ATP.^4,7 As a result, the concentration of sodium within the cell will increase and there will no longer be a sufficient concentration gradient (Fig 3). Finally, the third proposed mechanism is a defect in the cell membrane’s physical structure.⁸ The lack of either the concentration gradient or the defect in co-transports will leave sodium and other solutes in the tubular lumen, and these solutes are lost in the urine. The defects do not completely disable either the ATPase or the transport systems, but rather decrease their efficiency.

Gallery of Figures 1, 2 and 3 >>

Diagnosis of Fanconi's Syndrome

A dog suffering from Fanconi’s syndrome typically presents with polyuria and polydypsia, a history of weight loss, a poor hair coat and, sometimes weakness.^1,4 The diagnosis of Fanconi's syndrome is strongly suggested by the detection of glucosuria in the face of normoglycemia.^1,2,4,8 As stated previously, in normoglycemic conditions 100% of glucose should be resorbed in the proximal renal tubule. In the normal dog, the glucose co-transport system can tolerate glucose blood concentrations up to approximately 180 mg/dl before having glucose spill into the final renal filtrate.⁹ With all of the cotransporter and antiporter systems there is a maximum level at which the transports can work called the transport maximum (T_m). Once the transport maximum is exceeded, the remaining solute is not absorbed and is lost in the urine. In Fanconi’s syndrome, the T_m is reduced for the various solutes. The degree to which it is reduced varies between affected individuals and also varies according to the stage of the disease (Table 1).

Table 1. Differences in solute resorption in healthy dogs versus dogs with Fanconi syndrome.

*The above table assumes normal plasma levels for the solutes.

Other clinical findings in dogs with Fanconi syndrome may include a slight to mild proteinuria and a secretion-type metabolic acidosis (normal anion gap) with an alkaline urine (renal tubular acidosis).⁴

Consequences of Fanconi’s Syndrome

Fanconi’s syndrome is a progressive disease, which, if not treated, ultimately results in transport system failure to the point where solute losses are significant enough to overwhelm other compensatory mechanisms and the dog can no longer maintain homeostasis. The most significant of these is the loss of bicarbonate (HCO₃^-). Proximal renal tubular acidosis subsequently develops and, if left uncorrected, will ultimately lead to death. In an unaffected dog with a normal acid-base balance, most of bicarbonate ions in the urine are converted to carbonic acid (HCO₃^- + H⁺à H₂CO₃), which is then converted to H₂O and CO₂ with the aid of carbonic anhydrase found in the brush border of the renal tubular epithelial cell. The carbon dioxide formed readily diffuses across the luminal membrane of the renal tubular cell. In this way, bicarbonate is conserved.⁷ The hydrogen ion needed to form carbonic acid is supplied by the sodium-hydrogen ion antiporter, which has a high enough T_m to conserve the needed bicarbonate in an unaffected dog. In Fanconi’s syndrome, the T_m is reduced due to either the lack of a sufficient sodium concentration gradient or a defect in the transporter itself. As a result, fewer hydrogen ions are secreted and, thus, less bicarbonate is conserved. The loss of bicarbonate causes an acidemia and the plasma bicarbonate level decreases until it has reached a level which the impaired transport system can handle. Affected dogs can compensate somewhat for the acidemia through respiratory mechanisms (hyperventilation), shifts in intracellular potassium, and secreting hydrogen ions in the distal renal tubule.

Treatment

The treatment of Fanconi’s syndrome must be based on each individual as the severity of the disease is quite variable. The most important aspect of treatment is managing the metabolic acidosis.¹⁰ This can be very difficult due to the large quantities of bicarbonate being lost in the urine. The traditional treatment for Fanconi’s syndrome is administration of potassium citrate.^2,4 Poor results from potassium citrate treatment alone, however, has lead to a more extensive treatment to compensate for renal bicarbonate losses, the “Gonto protocol.” For an extensive explanation of this treatment, see: http://www.zandebasenjis.com/protocol.htm In a recent study, Basenji dogs with Fanconi’s syndrome treated by this protocol were found to have lifespans similar to dogs without Fanconi’s syndrome.¹¹ Bicarbonate concentration should be used to monitor the success of the alkali supplementation. Supplementation should be provided lifelong, as the affected dogs continuously lose bicarbonate into the urine. The increased amount of solutes in the urine causes an osmotic diuresis and an inability to concentrate urine. Therefore, it is important that affected dogs always have access to water.

References

1. Bovee KC, Joyce T, Reynolds R, et al. Spontaneous Fanconi syndrome in the dog. Metabolism 27: 45-52, 1978.

2. Bartges JW. Disorders of renal tubules. In: Ettinger SE: Textbook of Veterinary Internal Medicine. Diseases of the Dog and Cat. W.B. Saunders Co., Philadelphia, 2000, pp.1708-1709.

3. McNamara P, Rea C, Bovee K, et al. Cystinuria in dogs: Comparison of the cystinuric component of the Fanconi syndrome in Basenji dogs to isolated cystinuria. Metabolism. 38: 8-15, 1989.

4. Brown SA. Fanconi’s syndrome inherited and acquired. In: Kirk R. Current Veterinary Therapy. W.B. Saunders Co., 1989, pp. 1163-1165.

5. Brown SA, Rakich P, Barsanti J, et al. Fanconi syndrome and acute renal failure associated with gentamicin therapy in a dog. J Am Animal Hosp Assoc 22: 635-640, 1986.

6. Noonan CH, Kay J. Prevalence and geographic distribution of Fanconi syndrome in Basenjis in the United States. J Am Vet Med Assoc 197: 345-349, 1990.

7. Ganong W. Review of Medical Physiology. McGraw Hill Co., NY, 2001, pp. 675-695.

8. Hsu B, McNamara P, Mahoney S, et al. Membrane fluidity and sodium transport by renal membranes from dogs with spontaneous idiopathic Fanconi’s syndrome. Metabolism 41: 253-259, 1992.

9. Latimer KS, Mahaffey EA, Prasse KW (eds). Duncan & Prasse’s Veterinary Laboratory Medicine: Clinical Pathology, 4th ed. Iowa State Press, Ames, Iowa, 2003, p. 183.

10. Gonto S. Fanconi disease management protocol for veterinarians. http://www.basenji.org/fanconiprotocol2003.pdf January 28, 2004.

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