Normal Development

The development of the kidney is complex. There are three stages of development: the pronephros, mesonephros, and metanephros (Table 38-1). A schematic diagram of this process is illustrated in Figure 38-1. Nephrogenesis continues for at least 2 weeks postnatally in the dog. In newborns, the inner glomeruli are larger than those in the outer cortex. However, all cells within the proximal convoluted tubules have a significantly smaller membrane area than the adult. These differences gradually disappear as the kidney grows.

TABLE 38-1 Developmental embryology of the kidney

Stage	Description
Pronephros	• Cells of the intermediate mesoderm separate into an outer parietal and inner visceral layer forming the nephrocele. • Cords of cells extend from the parietal layer at the level of each somite and eventually become pronephric tubules. These tubules extend laterally and caudally until they join one another and form the pronephric duct. • Branches from the aorta form the glomeruli. Some glomeruli invaginate into the celom and become external glomeruli, and others invaginate into the pronephric tubules, becoming internal glomeruli.
Mesonephros	• The intermediate mesoderm in the thoracolumbar region proliferates and extends into the celomic cavity, forming the urogenital ridge. • The urogenital ridge will divide into the medial genital and lateral urinary ridge. Within the urinary ridge, the pronephric tubules stimulate the formation of the mesonephric tubules from invagination of the celom. • The medial aspect of the mesonephric tubule will invaginate and form Bowman’s capsule. The lateral aspect of the mesonephric tubule joins the pronephric duct (now termed the mesonephric duct). As the mesonephric tubules and ducts develop, the pronephric ducts and tubules atrophy.
Metanephros	• The metanephric blastema develops within the sacral mesoderm. Ureteric buds develop from mesonephric ducts in the caudal embryo and extend cranially to the metanephric blastema. The ureteric bud becomes the collecting ducts and renal pelvis. • The previously described mesonephric ducts become metanephric ducts. A portion of the metanephric blastema, or tissue, becomes the rest of the tubular system (proximal convoluted tubule, loop of Henle, distal convoluted tubule) and joins the metanephric duct and Bowman’s capsule to the collecting ducts formed by the ureteric buds. • The remainder of the surrounding metanephric blastema, or tissue, develops into the renal parenchyma.

Figure 38-1 Schematic representation of nephrogenesis.

(Modified from Zoetis T, Hurtt ME: Species comparison of anatomical and functional renal development, Birth Defects Research 68(B):112, 2003.)

In cats, normal renal development can be permanently altered by taurine deficiency. In addition to a decreased size, which is apparent by 8 weeks of age, kittens from dams with taurine deficiency have ureteral dilatation, large sclerosed glomeruli, proximal tubular flattening, epithelial atypia, reduced mitochondria at the apex of the tubule, and simplification of the tubule compared with age-matched controls.

The epithelial lining of the urinary bladder and urethra is endodermal in origin. The urinary bladder originates from the cloaca. The urorectal septum forms in the cloaca, which separates the rectum dorsally from the urogenital sinus ventrally. The cranial urogenital sinus becomes the vesicourethral canal and urinary bladder. The caudal urogenital sinus becomes the penile urethra in the male and urethra and vestibule in the female. The mesonephric ducts enter the dorsal aspect of the urogenital sinus in what becomes the trigone.

Physiology

Excretion and Reabsorption

During development, urine and wastes excreted by the fetal kidneys pass from the developing urinary bladder through the urachus into the allantoic cavity of the placenta. Waste products are then absorbed into maternal circulation. At birth, the neonatal puppy and kitten kidney is immature in both structure and function. Functionally the newborn has a lower glomerular filtration rate (GFR), renal plasma flow, and filtration fraction compared with the adult. The GFR increases with age postnatally. Glomerular capillary surface area and pore density increase between the first and sixth weeks after birth. Studies suggest that GFR and renal blood flow increase up to 11 weeks of age in the puppy and up to 9 weeks of age in the kitten before reaching adult levels.

There is limited evidence that puppies are capable of concentrating and diluting their urine at birth. When measuring urine-specific gravity, the urine may not be maximally concentrated, particularly in puppies less than 4 weeks of age, but this may be a reflection of the water content in their diet rather than an inability to concentrate their urine. Puppies also produce a higher daily urine volume and have an increased extracellular fluid volume compared with adult dogs. The urine and plasma osmolality in puppies and kittens increases with age and reaches adult values by 11 weeks of age in the puppy and 13 to 19 weeks of age in the kitten.

Neonatal renal handling of water and electrolytes differs from adults. The fractional reabsorption of water in dogs is constant, whereas sodium excretion increases during the first 3 weeks. Increases in renal arterial blood pressure are associated with increases in both absolute and fractional sodium excretion by adult and newborn dogs. In puppies, the fractional excretion of potassium and phosphorus decreases between 9 and 27 weeks of age, whereas the fractional excretion of chloride and calcium increases in the developing puppy. Despite these findings, the fractional excretion of all electrolytes in the puppies in these studies was within the normal range established for adult dogs. When the fractional excretion of sodium, potassium, chloride, phosphorus, and calcium was evaluated in kittens from 4 to 30 weeks of age, the only significant change observed during the study period was an increase in fractional excretion of potassium, but all values were within adult reference ranges.

Postnatal excretion of uric acid decreases from 83% at birth to 51% by 90 days of age. Similar to human infants, the decrease in uric acid excretion with age appears to be unrelated to binding of uric acid to plasma proteins or to urine flow rate. The amount of protein in the urine is higher in newborn puppies but decreases within the first few months of life. Possible contributors to proteinuria include colostral proteins absorbed within the first few days of life, increased filtration by immature and fewer glomeruli, decreased renal tubular reabsorption, alkaline urine, urine concentration, and protein from cells in the urinary tract.

Micturition

Micturition in neonatal dogs and cats is mediated by a spinal somatovesical reflex that is initiated by perineal stimulation. The dam initiates urination by licking the perineum and consumes the excreted waste, which keeps the neonate and the environment clean and dry. The somatovesical reflex pathway disappears between 3 and 5 weeks of age and is replaced by a vesicovesical reflex, which is a supraspinal reflex pathway that is activated by bladder distention and is under voluntary control. This is also the age at which postural control develops, which enables the puppy or kitten to assume a proper stance for urination. Unanesthetized puppies and kittens less than 3 weeks of age do not evoke bladder contractions despite pressurized bladder distention. If the perineum is not stimulated, the bladder will continue to fill, causing abdominal distention.

Examination of the Urinary System

Physical examination of the patient with urinary tract disorders may reveal urinary incontinence, lower urinary tract symptoms, or clinical signs of renal insufficiency or failure. Urinary incontinence may be intermittent and only noticed after the animal lies down for prolonged periods, or the incontinence may be more persistent, resulting in urine dribbling. When urine dribbling is noted, it is important to differentiate true incontinence from dribbling caused by overdistention, such as can be seen with urethral obstruction or neurologic bladder.

Lower urinary tract signs include pollakiuria, dysuria, stranguria, and hematuria. Lower urinary tract signs in young dogs and cats are seen most frequently with infections or calculi as a result of a congenital disease. Hematuria may be the only historic finding in diseases such as renal telangiectasia and idiopathic hematuria. If hemorrhage is severe, blood clots may form and lead to urinary tract obstruction. Anemia may also occur in dogs with idiopathic hematuria and renal telangiectasia.

Clinical signs of renal insufficiency include lethargy, poor growth, poor haircoat, weight loss, polydipsia, polyuria, and nocturia. With progression to renal failure, signs of uremia are seen, including anorexia, dehydration, pale mucous membranes, oral ulceration, halitosis, vomiting, hematemesis, diarrhea, melena, and death. Kidneys may be palpably enlarged with polycystic kidney disease. In most dogs and cats with primary renal disease, kidneys may be normal or small in size. Signs related to renal secondary hyperparathyroidism are more common in young dogs because their bones are more metabolically active. These signs include enlargement of the maxilla and mandible, a pliable mandible, bone pain, and pathologic fracture.

Hematologic and biochemical abnormalities are most often seen in animals with renal failure and include azotemia, hyperkalemia, hyperphosphatemia, and metabolic acidosis. Regenerative anemia is occasionally found with renal failure as a result of gastrointestinal ulceration and hemorrhage. Regenerative anemia also occurs in cases of significant blood loss through the urinary tract as seen with idiopathic hematuria and renal telangiectasia. In cases of chronic renal failure, nonregenerative anemia may be present.

Examination of the urine may be normal or reveal isosthenuria, proteinuria, glucosuria, hematuria, crystalluria, pyuria, and/or bacteriuria. Urinary fractional excretion of electrolytes may be abnormal with some tubular disorders. Urine culture is indicated in cases of suspected infection of the upper or lower urinary tract.

Diagnostic imaging of the urinary system includes plain radiography, contrast radiography, ultrasonography, and cross-sectional imaging. Plain radiographs may be used to evaluate the size and position of the kidneys and urinary bladder. This may be difficult in emaciated animals or in the presence of peritoneal or retroperitoneal fluid. Soft tissue mineralization and certain types of calculi may also be visualized on plain radiographs.

Contrast studies of the urinary tract include excretory urography, antegrade pyelography, and retrograde contrast administration. Typically this is done with iodinated contrast agents. Excretory urography can be used as a crude measure of renal function because excretion of the contrast agent depends on renal blood flow, GFR, and tubular reabsorption of water. Most commonly, excretory urography is used to evaluate the kidneys and ureters for position and filling defects. With antegrade pyelography, iodinated contrast is injected directly into the renal pelvis in an attempt to identify lesions of the ureter.

Retrograde contrast studies involve placement of a balloon catheter distal to the area of interest, followed by administration of an iodinated contrast agent. This technique can be used to evaluate lesions in the vagina, urethra, urinary bladder, and distal ureters. With double-contrast cystography, iodinated contrast agent and air are administered through a urinary catheter. This is typically done to evaluate the wall of the urinary bladder for thickening or mass lesions, as well as its contents (e.g., calculi). However, care must be taken when placing any type of urinary catheter in a pediatric patient because of the possible risk of iatrogenic urethral perforation.

Transabdominal ultrasound is used primarily to evaluate the kidneys, urinary bladder, and proximal urethra. Ultrasound is a useful determinant of size and echotexture of the kidneys, as well as a means of identifying filling defects. The renal pelvis can be evaluated for dilation, calculi, and mineralization. Normal ureters are poorly visualized with ultrasound because of their small size, but if they are dilated, as can occur with an obstruction, they can usually be visualized with ultrasound. Occasionally the opening of the ureters into the urinary bladder can be seen as the expulsion of urine from the ureters into the urinary bladder. The urinary bladder wall can be assessed for abnormalities and the vesicular contents seen. Although transabdominal ultrasonography can be used for the proximal urethra in females and prostatic urethra in males, transrectal ultrasonography is necessary for the more distal portion of the female urethra and prostatic and pelvic portions of the male urethra in the dog.

Magnetic resonance imaging and computed tomography are occasionally used when developmental abnormalities are suspected. Computed tomography using intravenous urography is believed to be superior to traditional contrast radiography for the diagnosis of ectopic ureters.

Flexible and rigid endoscopy has both diagnostic and therapeutic implications in diseases of the urinary tract. Endoscopy allows visualization of the vagina, urethra, and urinary bladder of dogs and cats. Endoscopy can also be used to aid in obtaining biopsies, in performing urethral injections of collagen in cases of urinary sphincter incompetence, and in performing urethral and vesicular lithotripsy and stone removal.

Biopsy is necessary to definitively diagnose many primary renal disorders such as glomerulonephropathies, amyloidosis, and renal dysplasia. Biopsy is also indicated for definitive diagnosis of mass lesions within the urinary tract. In cases of recurrent urinary tract infections, biopsy of the urinary bladder wall may be indicated to identify deeper tissue infections.

Congenital Disorders

Some congenital diseases are incompatible with life, and clinical signs of renal failure develop within the first few weeks of life. However, most of the diseases are not immediately life threatening, and clinical signs might not be apparent for several months or even years. The majority of congenital diseases manifest with urinary incontinence, lower urinary tract signs, renal insufficiency, or chronic renal failure.

Congenital disorders of the urinary tract may be caused by the presence of one or more abnormal genes. The end result may be production of an abnormal protein, failure to produce a normal protein, or production of excess amounts of a normal protein. In some instances, these mutations result in clinical syndromes that are sometimes identified in related animals. Familial or hereditary genetic diseases occur when a disease-causing gene is passed from one or both parents to offspring. The mode of inheritance is known for some of these diseases but not for others. Heritable diseases of the urinary tract have been identified in several breeds of dogs (Table 38-2) and cats (Table 38-3) and should be suspected when any of these breeds present with signs consistent with urinary tract disease. Newly affected breeds continue to be identified, and some of these conditions have been found in mixed-breed dogs and cats; therefore it is important that heritable diseases are not ruled out exclusively by signalment.

TABLE 38-2 Canine familial or heritable urinary tract disorders

Breed	Disorder	Trait
Alaskan Malamute	Renal dysplasia
Basenji	Fanconi’s syndrome	Familial
Bernese Mountain Dog	Membranoproliferative glomerulonephritis	Autosomal recessive
Beagle	Renal agenesis	Familial
Membranoproliferative glomerulonephritis	Familial
Border Terrier	Renal dysplasia
Fanconi’s syndrome
Boxer	Renal dysplasia	Familial
Brie Sheepdog	Renal dysplasia
Brittany Spaniel	Membranoproliferative glomerulonephritis	Autosomal recessive
Bull Terrier	Glomerulopathy	Autosomal dominant
Polycystic kidney	Autosomal dominant
Bulldog	Renal dysplasia
Bullmastiff	Glomerulonephropathy	Autosomal recessive
Renal dysplasia
Cavalier King Charles Spaniel	Renal agenesis
Xanthinuria Renal dysplasia + agenesis
Chinese Shar-Pei	Amyloidosis
Chow Chow	Renal dysplasia	Familial
Cocker Spaniel	Renal dysplasia–related?
Dachshund	Xanthinuria
Dalmatian	Glomerulopathy	Autosomal dominant
Uric aciduria	Recessive
Doberman Pinscher	Renal agenesis	Familial
Glomerulopathy	Familial
Dutch Kooiker	Renal dysplasia	Familial
English Bulldog	Renal and ureteral duplication
	Uric aciduria
	Ectopic ureter
	Urethrorectal fistula
English Cocker Spaniel	Glomerulopathy	Autosomal recessive
English Foxhound	Amyloidosis
Finnish Harrier	Renal dysplasia	Familial
Fox Terrier	Ectopic ureter
German Shepherd Dog	Multifocal renal cystadenocarcinoma	Autosomal dominant
Golden Retriever	Renal dysplasia	Familial
Ectopic ureter
Great Dane	Renal dysplasia
Labrador Retriever	Ectopic ureter
Lhasa Apso	Renal dysplasia	Familial
Miniature Poodle	Urethrorectal fistula, urethroperineal fistula, urethral duplication
Miniature Schnauzer	Renal dysplasia	Familial
Fanconi’s syndrome
Newfoundland	Glomerulopathy	Familial
	Cystinuria	Autosomal recessive
	Ectopic ureter
Norwegian Elkhound	Fanconi’s syndrome
Pekingese	Renal agenesis
Pembroke Welsh Corgi	Ectopic ureter
Renal telangiectasia
Poodle	Ectopic ureter
Rhodesian Ridgeback	Renal dysplasia
Rottweiler	Glomerulopathy	Unknown
Samoyed	Renal dysplasia
Glomerulopathy	X-linked
Scottish Terrier	Cystinuria	Autosomal recessive
Shetland Sheepdog	Renal agenesis	Familial
Fanconi’s syndrome
Shih Tzu	Renal dysplasia	Familial
Siberian Husky	Ectopic ureter
Skye Terrier	Ectopic ureter
Standard Poodle	Renal dysplasia	Familial
West Highland White Terrier	Ectopic ureter
Soft-Coated Wheaten Terrier	Renal dysplasia	Familial
Membranoproliferative glomerulonephritis	Familial

TABLE 38-3 Feline familial or heritable urinary tract disorders

Breed	Disorder	Trait
Abyssinian	Amyloidosis	Autosomal dominant with variable penetrance?
Domestic Shorthair	Renal agenesis
Oriental Shorthair	Amyloidosis
Siamese	Amyloidosis
Persian	Polycystic kidney	Autosomal dominant