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

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