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Diseases of the Kidneys
Urs Giger, Diplomate ACVIM & ECVIM
Veterinary Hospital, University of Pennsylvania
Philadelphia, PA, USA
penngen@vet.upenn.edu
P: 1 215 573 6109 office
F: 215 573 2162
www.vet.upenn.edu/penngen

18288599

Hereditary disorders involving the kidneys are being recognized with increasing frequency in companion animals. Recent advances in clinical laboratory diagnostic techniques and comparative genetic studies permit not only a clinicopathologic, but in many cases also a biochemical and molecular diagnosis. Some represent specific renal defects, whereas others lead to multisystemic organ failure. This presentation provides an overview on the diagnosis of hereditary kidney disorders (Table 1) and focuses on cystinuria.

Classification

 Developmental anomalies, e.g., renal dysplasia

 Metabolic renal transport defects, e.g., cystinuria

 Inflammatory renal processes, e.g., glomerulonephritis

 Familial renal cancer, e.g., renal cystadenocarcinoma

These hereditary diseases commonly manifest at a juvenile age, but may not cause signs until middle age. With the exception of urolithiasis the clinical signs are chronic progressive. Furthermore, renal disease may be associated with manifestations of other organ failures and anemia. Finally, certain defects of other organs may primarily trigger urologic clinical signs, such as urate calculi in Dalmatians. Although the clinical signs of hereditary renal disorders are vary heterogeneous, they can be divided into the following key signs:

 Polydipsia and polyuria

 Morphologic changes of the kidneys

 Uremia

 Nephrotic syndrome

 Urinary incontinence

 Urolithiasis and urinary track obstruction

Most disorders of the kidneys are inherited by an autosomal recessive trait. It has to be considered that for instance, the polycystic kidney and liver diseases in West Highland white and Cairn terriers is recessively, but the polycystic kidney disease in Persian cats is dominantly inherited. The unusual Alport nephropathy in Samoyeds is the only known disorder in companion animals that is inherited by an X-chromosomal dominant mode. Based on the gender differences in the urogenital anatomy incontinence is more frequently seen in bitches and urinary obstruction more commonly in males.

The general diagnostic approach to hereditary and acquired renal diseases is basically the same. Routine blood and urine tests are complemented with various imaging studies such as contrast radiology and ultrasonography to define development anomalies. Once a developmental defect has been discovered it is well possible that there are others present. In case of significant proteinuria a histopathologic examination of a renal biopsy may be indicated in order to better differentiate the various forms of glomerulonephropathies. Urine sediment and crystallographic analysis of uroliths helps in identifying causes for bladder and kidney stones. Furthermore, biochemical studies allow the characterization of the metabolic basis of renal transport defects, such as Fanconi syndrome, Glucosuria without hyperglycemia, and cystinuria. The Metabolic Genetic Screening Laboratory at the Veterinary School of the University of Pennsylvania has established a service to assist veterinarians when they suspect to have a patient with a novel genetic biochemical defect; samples from abroad need to follow special import instructions for the United States (http://www.vet.upenn.edu/penngen).

Recently molecular genetic screening tests have become available for a few hereditary renal disorders. These include mutation-specific DNA tests for cystinuria type I and linkage tests for multifocal renal cystadenocarcinoma in German Shepherds and for renal dysplasia in terrier breeds (information incomplete).

Cystinuria

Cystinuria is a common hereditary disorder in many canine breeds and rarely in cats caused by a renal transport defect of cystine and other dibasic amino acids. Because cystine precipitates in acidic urine, cystine crystals and calculi can form. These are responsible for mild to life-threatening clinical signs related to urinary tract irritation and obstruction. The diagnosis was based upon identification of hexagonal crystals in the urinary sediment, crystallographic calculi analysis, and the cyanide nitroprusside test for cystine in urine samples. However these test can only detect affected, i.e., cystinuric animals.

Although cystinuria causes predominantly clinical signs in male dogs, cystinuria has been shown to be inherited by an autosomal recessive and not X-chromosomal trait in at least the Newfoundland and Labrador retriever breed just like in humans. Furthermore two different mutations in the renal basic amino acid transport gene (rBAT protein) have been identified to cause cystinuria in Newfoundlands and Labradors. This allowed the development of a molecular screening test that can identify cystinuric and carrier animals. We have surveyed over 1300 Newfoundland dogs in the United States and with the assistance from Dr. Dreier from Baden, Austria we have also screened nearly 100 Newfoundland dogs in Europe and discovered a high frequency of the mutant allele. Whereas only 1% was affected, approximately 20% of all tested Newfoundland dogs carried the mutant allele; these dogs can pass the disease-causing gene on to the next generation if they are used for breeding. Thus we recommend to DNA-test all Newfoundlands or Labradors with suspicious clinical signs, relatives of cystinuric Newfoundlands and Labradors, and any Newfoundland intended to use for breeding. Whereas the American Kennel Club and most others breed clubs have no means to enforce testing, the Austrian Newfoundland club does require testing of breeding animals. It is hoped that additional molecular tests can be developed for other breeds affected with cystinuria. Our preliminary studies suggest that there may be another transport protein involved. Until then these breeds can only be surveyed by the biochemical tests that discover cystine in urine. Unfortunate, the lack of a DNA test for carrier detection in most breeds and the continued reluctance to screen breeding animals hamper the eradication of cystinuria from affected breeds. Further research and educational efforts for veterinarians and breeders will hopefully soon lead to the eradication of these single gene defects.

Table 1. Hereditary renal disorders

Disease

Inheritance

Species, Breeds

Development anomalies

Juvenile renal dysplasia

AR

many canine breeds

Polycystic kidney disease

AD

Persian

Cystic renal & liver disease

AR

West Highland White & Cairn terrier

Hereditary nephritis

AR

Cocker Spaniels

X-chromosomal Nephropathy

XD*

Samoyed

Dominant Nephropathy

AD

Bull terrier

Metabolic Defects

Cystinuria type I

AR*

Newfoundland, Labrador

Cystinuria other

U

many canine breeds, some cats

Glucosuria

U

Norwegian Elkhound

Renal Fanconi syndrome

U

Basenji

Primary Hyperoxaluria

AR

Tibetan terrier

Essential hypertension

U

German Shepherd

Nephrogenic diabetes insipidus

XR

Husky

Inflammatory processes

Amyloidosis

U

Shar Pei,

Abyssinian, Oriental shorthair

Glomerulonephropathy

U

Bernese mountain dog

female Doberman pinscher

Glomerulonephropathy and enteropathy

U

Soft coated Wheaten terriers

Hyperimmune enteropathy and glomerulonephropathy

U

Basenji

Familial glomerulonephropathy

U

Bullmastiffs

Familial neoplasia

Multifocal renal cystadenocarcinoma and nodular dermatofibrosis

German shepherd

AR, autosomal recessive; XD x-chromosomal dominant; XR, x-chromosomal recessive; U, unknown

Speaker Information
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Urs Giger, ACVIM & ECVIM
University of Pennsylvania
Philadelphia, PA, USA

Giger

Urs Giger was born and raised in Zürich, Switzerland, and because of his interest in horses, he studied veterinary medicine. He received his veterinary degree from the University of Zürich, Switzerland in 1977, where he also pursued his initial clinical training in small animal medicine and surgery and a doctoral thesis on the orthopedic correction of canine hip dysplasia. He was accepted into a one-year Postgraduate Course of Experimental Medicine and Biology and worked on his first basic science research project in pharmacogenetics at the University Hospital of the University of Zürich. Thereafter, he moved as a postdoctoral fellow to the United States, where he subsequently completed a residency in small animal medicine at the University of Florida.

He joined the faculty of the School of Veterinary Medicine at the University of Pennsylvania in Philadelphia in 1984 and has been a clinician and teacher in medicine, hematology, pediatrics, and medical genetics. He is now the Charlotte Newton Sheppard Professor and Chief of Medical Genetics and has a secondary faculty appointment at the Medical School of the University of Pennsylvania. In addition, he is also a professor at the Veterinary School of the University of Zürich, where he regularly lectures on small animal internal medicine, and is a frequent invited speaker at international veterinary conferences. He is a diplomate of the American as well as the European College of the Veterinary Internal Medicine and is heading the Pediatrics and Genetics Clinic, the Josephine Deubler Genetic Disease Testing Laboratory, and the Transfusion Medicine Program at the University of Pennsylvania thereby providing unique veterinary services.

His research expertise and interests are in two, somewhat overlapping areas: 1) characterization of hereditary disorders of small animals from clinical signs to the molecular genetic defect and to develop accurate laboratory test to identify disease-causing mutations; 2) diagnosis of hematologic disorders with novel tools and their management particularly with transfusion therapy and emphasis on blood compatibility and safety issues. His clinical and basic research studies have been published in over 200 original and review papers.

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