Hereditary Kidney Disease

WHAT IS RENAL DYSPLASIA? Renal dysplasia is a developmental or genetic defect of the kidneys. This makes it quite different from common forms of kidney disease which occur in adult or aged dogs and from other diseases, drugs and/or poisons which may cause inflammation of the kidneys and abnormal results on blood and urine test of kidney function. It is found most commonly in Shih Tzu and Lhasa Apsos.

The dog is born with relatively immature kidneys. This changes rapidly in the first six weeks of life. In many animals, immature nephrons (urine-forming units) exist until 6-10 weeks of age. But in this disease, these immature nephrons persist throughout life. Also, some nephron units do not develop and are replaced with fibrous tissue. Sometimes this fibrous tissue represents 20-50% of the kidney, and the kidneys are noticably small and irregular. (Fig.1 ) Other evidence of renal dysplasia includes diffuse interstitial fibrosis in the cortex and medulla (which seems quite peculiar to this disease), reduced numbers of glomeruli (the filtering structure of the kidney where toxins, fluid and electrolytes are removed from the blood), dilated and hypoplastc tubules (through which the fluid or filtrate passes while it is being transformed into final urine), and a variety of sizes of glomeruli. Some glomeruli are 20-30% smaller than normal, some are normal size, and some are embryonic. (Fig. 2) While mineralization of tubules can be seen in any chronic renal disease, this mineralization is seen with renal dysplasia even in young animals that have only moderate uremia.

Researchers believe that this mineralization is somehow an early component of this disease and is related to the abnormal development of the nephrons. Dogs with renal dysplasia have had an embryonic arrest some time around birth. Hypertension does not seem to be part of this disease.

Affected dogs are characterized by the percentage of hypoplastic glomeruli: Dogs with 1-2% hypoplastic glomeruli are borderline. Dogs with 2-15% are mild. Dogs with 15-25% are moderate. Dogs with 25-35% are moderately severe. Dogs with over 35% hypoplastic glomeruli are severe.

Beyond severe is "end stage kidney", a real diagnostic problem. Dogs in this stage have such severe histologic change that the presence of dysplasia can be obscured. Dr. Kenneth C. Bovee of the University of Pennsylvania, who has conducted several hundred biopsy examinations on closely and distantly bred animals over the past 15 years, only feels comfortable with diagnosis when dealing with animals affected up to about 35% abnormal nephrons.

WHAT ARE THE SYMPTOMS AND TREATMENT? The common denominator in various forms of kidney disease is always the reduced numbers of functional nephrons to perform metabolic activity. Three stages, each of which may have a variable and independent time course, characterize the usual progression of most kidney diseases due to various causes. Stage one is the silent destruction and loss of nephrons over a period of months or years in the absence of symptoms. Stage two occurs when approximately 30% of functioning nephrons remain and clinical symptoms are first obvious. These symptoms include excessive thirst and volume of urine, weight loss, lack of vigor, and intermittent loss of appetite. This stage may persist for months or years. In many cases excessive drinking and urination are the major symptoms. The final stage is termed renal failure or uremia. To second-stage symptoms are now added vomiting, weakness, dehydration, and severe debilitation. In this latter stage, death is the eventual outcome.

The first symptoms may be observed in severely affected puppies immediately after weaning. Excessive thirst, excessive volume of urine, and pale urine may be noted at this time. Due to post-natal development of the kidneys, normal puppies produce a pale dilute urine until six weeks of age. One can become suspicious of renal dysplasia around eight weeks of age if excessive drinking is noticeable. Normal Shih Tzu and Lhasa Apso puppies drink approximately one ounce of water per pound of body weight when eight to ten weeks of age. Dogs with severe disease may drink as much as five times that quantity. Therefore, a simple measurement of water intake per unit of body weight might be helpful. (These figures are based on dogs that consume a commercial dry food; one cup of food mixed with 1/3 cup of water.)

Other symptoms occurring early in life in severely affected dogs include reduced body weight and stature compared to normals. Severely affected dogs will fail to thrive at two or three months of age and progress to renal failure quickly. Affected puppies commonly weigh less than three to five pounds at five months of age. The symptoms of severely affected puppies are essentially those described previously for stage two and the final stage of renal failure, most notably failure to grow, reduced appetite, weakness, anemia, and general debilitation. Not all puppies in a litter are uniformly affected.

Moderately affected puppies may appear normal until five or six months of age and then follow the same course, with chronic debilitation and death at nine to twelve months. The severely and moderately affected puppies can most easily be suspected by increased water intake and reduced body size. Since a standard growth rate curve is not available for these breeds, the latter consideration may not be helpful unless the dog is markedly undersize. The reduced stature and body weight is due to metabolic disturbances of uremia which affect bone growth. Marked skeletal abnormalities such as bowed long bones and soft pliable bones of the jaw may be found. It may be helpful for breeders to record normal weight curves to identify suspicious young dogs.

The classical symptoms of affected dogs just described would only be expected in severely and moderately affected dogs. The disease is poorly recognized because many animals are only slightly affected. They show no clinical signs and the presence of the disease in many mildly affected dogs may fail to be detected by routine laboratory tests, including urinalysis, serum creatinine, BUN, radiographs of renal size, and ultrasound. Many affected dogs with less than 10% of fetal glomeruli will live a normal life span with apparently normal renal function and can pass on some of the defect to their offspring. Due to the nature of this disease it can go undetected for many generations or be ignored by knowledgeable breeders because only a small percentage of animals are severely affected and will die of renal failure. the disease is going to be with us for a long time because it is transmitted in a very silent fashion by many animals that appear clinically normal.

The treatment of renal dysplasia is essentially the same as for any chronic renal failure disease. A recent study suggests that a low protein diet may have little effect in preventing or delaying the development of renal dysplasia. However, while diet may not alter the progression of the disease, phosphorus and protein-restricted diets are often recommended for dogs that have any form of kidney disease.   Protein restriction has not been shown to produce any benefit in altering the course of the disease, and may in fact be harmful.  Phosphorus restriction may help ameliorate its symptoms.

HOW IS IT INHERITED? Although renal dysplasia is clearly inherited, the genetic nature of this disease does not follow a classical Mendelian pattern. It is not sex-linked. Dr. Bovee's data is most consistent with autosomal dominant inheritance with incomplete penetrance or recessive inheritance.  Some statistical studies have now strongly suggested that two genes working together may be responsible for RD.

This explains many of the mysteries of RD. Imagine that RD is a door with 2 locks, the regular door lock and a deadbolt lock. In order to open the door I will need two keys. But I need the right two keys. Two door keys or two deadbolt keys will not do it. I need one of each.

If I mate a dog with RD1 to a bitch with RD1, the pups will have normal kidneys. if my dogs are highly linebred, and therefore highly homozygous for RD1, I will not have a problem until I outcross to a line which carries RD2. This explains how we can go along with healthy dogs for many years, and suddenly have a whole litter with renal dysplasia.

Affected adults will produce affected puppies whether one or both adults were considered positive. It seems safe to conclude that the majority of puppies produced by affected dogs will be affected to some degree, although this does not mean that all affected puppies will die of kidney failure. In rare instances, normal puppies, as judged by kidney biopsy will be produced by breeding affected dogs. The severity of the disease in offspring from slightly affected dogs is highly variable. These puppies may also be slightly affected, severely affected, or a few may be normal. In unusual instances, we have seen normal dogs, judged by diagnostic tests, produce affected puppies. In most instances, however, it is the lack of biopsies that has led to the greatest confusion about the presence or absence of this disease and the manner in which it is inherited. In almost all cases, Dr. Bovee has found one or both parents of a severely affected puppy to be affected based on biopsy.

HOW CAN WE TEST FOR IT? There are several tests for kidney function, although only one of them will specifically determine whether abnormal kidney function is due to renal dysplasia. BUN and Creatinine are two common blood tests of renal function. They are not elevated until 70-75% of the kidney is nonfunctioning and are therefore of little use in identifying mildly or moderately affected dogs. The BUN measures the blood-urea-nitrogen in the blood. When the kidney is not doing its job of removing these waste products from the blood they begin to build up in the bloodstream. The BUN test will then show an elevation of these waste products. The BUN can be elevated for other reasons which your veterinarian can explain. The creatinine test is a somewhat more accurate measure of renal function. This is because creatinine is not used by the body and all of it is excreted in the urine. By measuring the amount left in the blood, the filtration rate of the kidneys can be judged. The BUN and creatinine tests can be done from the same blood sample. Having a BUN and creatinine in the normal range means that the dog has at least 30% kidney function. It does not mean that the dog is free of renal dysplasia. Nor does an elevated BUN and creatinine mean that the dog necessarily has renal dysplasia, as such readings can be caused by other renal problems. Nevertheless, these tests can be of some use in identifying severely affected dogs, particularly puppies already drinking and urinating excessively.

Urine Specific Gravity can be measured by your veterinarian with an instrument called a refractometer. Only a couple of drops of urine are needed. Urine can be picked up from newspapers or floor with a syringe. Water has a specific gravity or weight of 1.000; normal dog urine has a specific gravity from 1.018 to 1.060. When a dog's kidneys are failing they usually produce a very dilute urine with a specific gravity of 1.010 to 1.020. (Note that these numbers will differ in countries where tests are based on the metric system. Ask your veterinarian to provide normal ranges.) Most veterinarians will tell you that all readings of urine specific gravity ranging froml.018to1.060 are absolutely normal. The ASTC Renal Dysplasia Committee has found that most adult Shih Tzu and Lhasa Apsos with normal kidneys usually have a specific gravity above 1.045. Again, the specific gravity of urine tells you about kidney function. It does not tell you that your dog is free of renal dysplasia.

Ultrasound Examination of the kidney, again, will not tell you whether or not your dog has renal dysplasia, but it may help to identify  moderately affected dogs with normal BUN, creatinine, and urine specific gravity readings and no clinical signs of the disease. In severely and some moderately affected dogs, an ultrasound may show scarring, smaller than normal kidneys that may be irregular in shape, and defects in the collecting ducts in the renal pelvis. An ultrasound-guided biopsy, which will help to ensure that the tissue is extracted from the most severely affected part of the kidney, is suggested if the ultrasound examination indicates that the kidneys are abnormal in ways associated with renal dysplasia. The ultrasound examination itself will not show the fetal glomeruli that provide definitive proof of renal dysplasia. Slightly affected dogs are likely to appear normal upon ultrasound examination.

X-rays to determine the size of the kidneys may be helpful. If both kidneys are markedly reduced in size, a presumptive diagnosis of dysplasia can be made. The size of affected kidneys will range from a reduction of 20% of normal to tiny, shrunken kidneys. Again, this is not a definitive diagnosis, particularly in older dogs that may have old-age kidney problems.

Biopsy of the kidney involves the surgical removal of a wedge-shaped section of kidney. A needle (trucut) biopsy does not supply enough tissue for diagnosis of renal dysplasia and therefore is of no value. There have been no known complications for the dog due to the wedge biopsy procedure, although there is a risk as there is with any surgery and anesthesia. Anesthetic should not be given to a dog with an elevated BUN, as such a dog is a surgical risk. The kidney biopsy is the most accurate method to date of determining if a dog has or does not have renal dysplasia. In a few cases a Shih Tzu or Lhasa Apso will be so mildly affected that even a kidney biopsy will show no signs of the disease.

The collection of the specimen of kidney tissue for microscopic examination can be performed by an experienced pathologist familiar with this disease.  Breeders can also submit kidneys from puppies that die mysteriously at a young age, but DO NOT send kidneys of puppies less than eight weeks old because their kidneys are not suffficiently developed to identify the disease. The kidneys must be collected from the animal immediately after death and placed in 10% formalin solution; freezing destroys the tissue and precludes a diagnosis. We also recommend that the kidneys of adult Shih Tzu or Lhasa Apsos that die for any reason be examined, even though the presence of other forms of kidney disease in older animals may at times preclude a definitive diagnosis.

WHAT CAN WE DO ABOUT IT? Every dog used for breeding should be tested for urine specific gravity and urine concentration. If specific gravity is above 1.045 (or the metric equivalent) you can skip the other tests and go right to the biopsy. If specific gravity is low then do BUN and creatinine tests. If these are elevated you may not want to risk anesthetic and the biopsy. Do as your vet advises. If urine and blood tests are normal and you are unwilling to do a biopsy, you may be able to detect the presence of the disease with ultrasound, although a normal ultrasound will not prove that your dog does not have renal dysplasia. While a biopsy may occasionally indicate that a slightly affected dog is normal or fail to pick up a normal carrier, there are no false positives. If a wide wedge biopsy indicates that the dog is affected, it is likely to pass the disease along to some or all of its offspring in varying degrees and should not be bred.