Update on Fanconi Syndrome and Cystinuria
World Small Animal Veterinary Association World Congress Proceedings, 2015
Urs Giger1, DACVIM (Small Animal Internal Medicine), DECVIM-CA, DECVCP; A. Brons2; K. Mizukami2; J. Slutsky2; K. Raj2; C.A. Fitzgerald2; S. Strickland2; A.C. Sewell3; P.S. Henthorn2
1Charlotte Newton Sheppard Professor of Medicine Chair, University of Pennsylvania, Philadelphia, PA, USA; Professor, University of Zürich, Zürich, Switzerland; 2University of Pennsylvania, Philadelphia, PA, USA; 3University Children's Hospital, Frankfurt, Germany

Urs Giger graduated from University of Zürich. At the University of Pennsylvania, Urs Giger has the endowed Charlotte Newton Sheppard Professor of Medicine chair. He is a diplomate of the American and European College of Veterinary Internal Medicine, as well as a diplomate of the European College of Clinical Pathology. He has a secondary professorship in small animal internal medicine at the University of Zürich. His clinical and research expertise and interests are in hereditary and hematologic disorders and are reflected in > 200 original publications. He is also chairing the WSAVA Hereditary Disease Committee and is the recipient of the 2002 WSAVA International Scientific Lifetime Achievement Award and the 2007 BSAVA International Bourgelat Award.


Introduction

Disorders of the renal proximal tubules can cause selective or generalized aminoaciduria and may be associated with urinary losses of other solutes such as glucose, lactate, electrolytes and bicarbonate. Two renal tubular defects involving amino acids have long been recognized in dogs (far less common in cats), namely cystinuria, leading to cystine calculi and urinary obstruction, and Fanconi syndrome, a generalized tubular defect progressing to renal failure if untreated. The current understanding of pathophysiology, clinicopathological findings, diagnosis and therapeutic options will be presented.

Fanconi Syndrome

Fanconi syndrome represents a major proximal renal tubular defect, which hampers the adequate reabsorption of glucose, amino acids, bicarbonate, sodium, calcium, phosphate, lactate, ketones and carnitine. This rather general loss of multiple functions of the proximal renal tubules can be associated with renal tubular acidosis and lead to progressive renal failure if left untreated. The mechanisms involved in Fanconi syndrome in dogs may include multiple genetic predispositions, acquired causes, or combinations of both. Basenjis are genetically predisposed to Fanconi syndrome, which is inherited as an autosomal recessive trait in the breed. As many as 10% of Basenjis are affected, and they typically develop signs in middle age (4–7 years). A mutation in the Fan1 gene has recently been discovered. Recent studies indicate that Labrador Retrievers with copper-associated hepatopathy develop Fanconi syndrome. More recently Fanconi syndrome has been associated with the ingestion of chicken and duck, and even veggie pet jerky treats of different brands that contain Chinese products. Currently no specific ingredient or contaminant responsible for the intoxication has been identified, but the FDA and state governments are actively investigating the jerky treats. Nearly all the dogs affected are from North America and Australia and, recently, also Europe. Affected dogs mostly include toy to small breed dogs, such as Chihuahuas; Maltese; and Yorkshire, Jack Russell and West Highland White Terriers, but not brachycephalic breeds (except Shih Tzus). Their predisposition may be related to the proportionally larger amount of jerky treats ingested by small breeds compared to large-breed dogs, or may reflect a broader hypersensitivity of the smaller breeds.

Clinical signs of intoxication may not be seen overtly or occur within days to months of ingesting jerky treats; are unspecific; and may include lethargy, inappetence, vomiting, and diarrhea. Polydipsia and polyuria are the most common clinical signs of Fanconi syndrome, while other signs of Fanconi syndrome are highly variable and may be related to the ensuing renal failure. In the past, a diagnosis of Fanconi syndrome resulted in a guarded to poor prognosis. However, in the present day, treated Basenjis may reach a near normal life expectancy. Moreover, if the trigger is removed, such as withdrawal of Chinese jerky treats, the renal damage may be more minimal and reversible. Routine serum chemistry and urinalysis as well as venous blood gas analyses are indicated to define the extent of the tubular defect and acidosis.

Routine urine dipstick analysis typically reveals glucosuria. Urine metabolic screening from dogs with Fanconi syndrome shows often massive generalized aminoaciduria and lactic aciduria (and the glucosuria and ketonuria also confirmed) (University of Pennsylvania; Metabolic Genetics Laboratory and Laboklin and Biocontrol, Germany) can document the aminoaciduria, the hallmark finding of Fanconi syndrome. Dogs with Fanconi syndrome have much higher urinary concentrations of cystine and dibasic amino acids in comparison to cystinuria, as well as exhibit massive excretion of all other amino acids. Moreover, while there is severe aminoaciduria, there is either no or only mild proteinuria. The University of Missouri offers DNA testing for Basenjis (www.caninegeneticdiseases.net).

The therapeutic protocol (www.basenji.org/ClubDocs/fanconiprotocol2003.pdf) was developed and modified over the years by Steve Gonto. It focuses on aggressive correction of the various losses with particular attention to bicarbonate, normalizing electrolytes and minerals, and providing a high quality diet. Bicarbonate is dosed to increase pCO2 and HCO3 levels. Dogs that ingested Chinese jerky treats are known to have improved and even resolved their metabolic derangements within a few weeks to months after withdrawing the treats, unless they had already developed severe renal damage and failure by the time of diagnosis. Labrador Retrievers and other dogs with copper-associated hepatopathy and Fanconi syndrome may also require copper chelation and low copper diets.

Cystinuria

Cystinuria is a limited hereditary renal transport disorder involving cystine and the dibasic amino acids ornithine, lysine, and arginine, collectively known as COLA. Instead of the normal > 99% reabsorption in the proximal renal tubules, these four amino acids are lost in the urine, but only cystine causes a problem. The low solubility of cystine in acidic urine predisposes the formation of cystine crystals and uroliths in the urinary tract, resulting in the typical clinical signs of cystinuria. Two genes, SLC3A1 and SLC7A9, encode the polypeptide subunits of the bo,+ basic amino acid transporter system and its dysfunction results in cystinuria. SLC3A1 encodes a protein referred to as rBAT and SLC7A9 encodes a protein called bo,+AT. bo,+AT heterodimerizes with rBAT exclusively to form the COLA amino acid transporter. Since 1823, when cystinuria was first described in dogs, dogs of many breeds have been diagnosed, but only recently have studies revealed the molecular genetic heterogeneity. A severe cystinuria showing autosomal recessive inheritance was first characterized in Newfoundlands/Landseers. Although both males and females are affected, males more frequently show clinical signs of urinary obstruction. Different mutations in SLC3A1 have been identified in Newfoundlands and Labrador Retrievers and, recently, a cat (Type I-A). A deletion in SLC3A1 was found in autosomal-dominant (AD) cystinuria with a more severe phenotype in homozygous than in heterozygous Australian Cattle dogs (Type II-A). A missense mutation in SLC7A9 was identified in autosomal dominant cystinuria in Miniature Pinschers from Europe, with only heterozygous affected dogs observed to date (Type II-B).

Cystinuria has also been described in an additional 70 canine breeds. In several of these breeds from which more data is available, such as the Mastiff, French and English Bulldog, Basset hound and Irish terrier, the disease predominantly occurs later in life, is less severe, more variable and only involves intact mature males. We now refer to this as canine androgen-dependent or Type III cystinuria but still do not know the specific genetic defect(s).

Androgen-dependent (Type III) cystinuric dogs (with or without cystine calculi) also seem to have variable degrees of cystine and COLA in their urine. An SLC3A1 missense mutation appears to be associated with cystinuria in Mastiffs and related breeds, but not Irish Terriers or Scottish Deerhounds. Only mature males are cystinuric and surgical (and even medical) castration resolves excessive cystine and COLA excretion, but the mode of inheritance is still unclear.

Cystine uroliths can form in the kidney (rarely), ureters, bladder or urethra and can lead to urinary blockage, renal failure and associated life-threatening clinical manifestations in dogs and cats. A clinical diagnosis of cystine uroliths can be suspected based upon the breed and yellow-brown color of the uroliths, and can be confirmed by crystallographic or chemical analysis of calculi in specialized stone laboratories. Cystine calculi are usually radiolucent and thus may be missed by radiography, but are readily visualized by ultrasound. Furthermore, urinalysis often reveals the presence of characteristic hexagonal cystine crystals.

A simple urinary screening test through the Metabolic Genetic Laboratory at the University of Pennsylvania (http://research.vet.upenn.edu/penngen/PennGenHome/tabid/91/Default.aspx) can detect any Type I and II cystinuric animal, but not necessarily all dogs with Type III cystinuria. Amino acid analyzers can be used to determine COLA values is preferred due to the possibility that urinary cystine may have precipitated. Based upon our studies, dogs with either cystine levels of > 200 µmol/g creatinine or COLA values of > 700 µmol/g creatinine are considered cystinuric. Moreover, for several breeds with Type I and II cystinuria, a breed-specific mutation test is available that not only detects cystinuric dogs, but also the asymptomatic carriers (for recessive traits). The WSAVA Hereditary Disease Committee established a web-based database for any DNA test for a hereditary disease in dogs and cats, which is available in a laboratory worldwide (http://research.vet.upenn.edu/WSAVA-LabSearch).

Urinary tract obstructions due to cystine calculi can present as life-threatening emergency situations. If the calculi are in the urethra, catheterization and endoscopy may allow their passage, permit them to be moved back into the bladder (retrograde hydropulsion). Laser therapy as well as lithotripsy may break them up, and surgery can be used to remove them entirely. A nonsurgical procedure is preferred. In contrast, attempts to dissolve cystine stones medically by drugs and diet have generally failed. Alpha-mercaptopropionylglycine (Thiola), a chelating agent that has fewer side-effects and is more potent than D-penicillamine, may lower the risk of calculi formation in cystinuria but is very expensive. Forced diuresis, urine alkalinization (pH > 7.5), and reduced protein diets (no chicken) may lower the recurrence risk. Male dogs with Type III cystinuria may or may not develop calculi and their recurrence rate is lower. Moreover, castration of Mastiffs and related breeds and Irish Terriers with Type III cystinuria diminishes the excretion of cystine and dibasic amino acids to the normal range.

Supported in part by grants from the National Institutes of Health (OD 010939) and the AKC Canine Health Foundation. LABOKLIN assisted in sample collection.

References

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2.  AVMA. Safety alert on jerky treats for pets. May 2014. www.avma.org/news/issues/recalls-alerts/pages/safety-alert-on-jerky-treats-for-pets.aspx.

3.  Brons AK, Henthorn PS, Raj K, Fitzgerald CA, Liu J, Sewell AC, Giger U. SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system. J Vet Intern Med. 2013;27:1400–1408.

4.  Carmichael N, Lee J, Giger U. Fanconi syndrome in dog in the UK. Vet Rec. 2014;174(14):357–358.

5.  Farias F, Mhlanga-Mutangadura T, Taylor JF, O'Brien DP, Schnabel RD, Johnson GS. Whole genome sequencing shows a deletion of the last exon of Fan1 in Basenji Fanconi syndrome. In: Proceedings from the Advances in Canine and Feline Genomics and Inherited Diseases Conference. Visby, Sweden; 2012. 51.

6.  FDA update. www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm360951.htm.

7.  Fieten H, Hooijer-Nouwens BD, Biourge VC, Leegwater PA, Watson AL, van den Ingh TS, Rothuizen J. Association of dietary copper and zinc levels with hepatic copper and zinc concentration in Labrador Retrievers. J Vet Intern Med. 2012;26:1274–1280.

8.  Hooijberg EH, Furman E, Leidinger E, Brandstetter D, Hochleitner C, Sewell AC, Leidinger J, Giger U. Transient renal Fanconi syndrome in a Chihuahua exposed to Chinese chicken jerky treats. Kleintierpraxis. 2015; in press.

9.  Gonto S. Fanconi disease management protocol for veterinarians. 2014. www.basenji.org/ClubDocs/fanconiprotocol2003.pdf.

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18. Slutsky J, Oliver JB, Fitzgerald CA, Store V, Sewell AC, Giger U. Results of urinary metabolic screening in dogs with acquired and hereditary Fanconi syndrome. Submitted.

19. Yearly JH, Hancock DD, Mealey KL. Survival time, lifespan and quality of life in dogs with Fanconi syndrome. J Am Vet Med Assoc. 2004;225:377–383.

  

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Urs Giger, DACVIM (Small Animal Internal Medicine), DACVIM, DECVIM-CA, DECVCP
Charlotte Newton Sheppard Professor of Medicine Chair
University of Pennsylvania
Philadelphia, PA, USA


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