Renal tubular disease

Question 1

Detail the genetics and signalment for dogs (and cats) with cystinuria

Answer 1

Condition arises from a defect in proximal tubular resorption of particular non-essential amino acids. Of these amino acids, cystine is relatively insoluble in urine

• Various dog breeds affected
  
  • Newfoundland, labrador, English bulldog, chihuahua, Staffy, Daschund, Rottweiler, Miniture punscher, JRT
• Various modes of inheritance in the different breeds
  
  • Genetic testing available for Newfoundland
• Mean age of calculus formation is 4.9 years
  
  • Labrador and Newfoundland as early as 4-6 months
• Males are over-represented

Clinical signs and diagnostics as for any other cause of dysuria with suspected calculi

Question 2

Describe the treatment approach for dogs with confirmed cystinuria urinary calculi

Answer 2

• Standard approach for obstructive or stones in the presence of bacterial cystitis
• Dissolution in the presence of low protein (low cysteine) diet and an alkali urine
• Twice as soluble at pH 7.8 when compared to pH 6.5
  
  • Potassium citrate if urine pH not appropriately high
• Urinary dilution likely to help
• 2-MPG forms thiol-cysteine bonds creating a more soluble form of cysteine.

Question 3

Briefly comment on the possibility of carnitinuria and carintine deficiency in conjunction with cystinuria

Answer 3

• Carnitine deficiency in dogs can occur with defective biosynthesis (potentially from a low protein diet), defective tissue uptake, or increased renal excretion
• Dogs with cystinuria may also excrete excessive carinitine
  
  • Carintinuria has been documented in this case
• High fat-low protein diets have been recommended for cystinuria
  
  • This diet can increase carnitine excretion in humans
• Carnitine deficiency could occur with cystinuria and a low protein diet

Question 4

Describe the metabolic pathway of the nucleic acid pruine

Answer 4

• Purine is metabolised to form hypoxanthine and xanthine
• Xanthine is oxidised to form uric acid by xanthine oxidase
• In most mammals, uric acid is metabolised to allantoin by hepatic uricase

Purine ⇒ xanthine (and hypoxanthine) ⇒ uric acid ⇒ allantoin

Question 5

Describe how purine metabolism in Dalmation dogs differs from non-dalmation dogs

Answer 5

• Purine metabolism in non-dalmation dogs typically leads to production of the waste product allantoin. Allantoin is readily soluble in normal urine
• Dalmation dogs have intermediate production of allantoin, with ~1/2 to 2/3 as much allantoin produced. Therefore uric acid is excreted in urine (as for humans)
  
  • Uric acid can form ions and salts known as urates - especially ammonium urate which are poorly soluble in urine
• Dalmation dogs have a normal amount of hepatic uricase, so when uric acid reaches the hepatocytes it is converted to allantoin as normal
• Dalmation dogs have a defect in proximal renal tubular reabsorption of uric acid leading to excessive quantities entering the urine
• They also have a missense mutation leading to a membrane defect in the distal convoluted tubule
  
  • This leads to secretion of urates

Question 6

Describe how dogs with reduced hepatic capacity develop ammonium urate calculi

Answer 6

• With reduced hepatic capacity, there is less availability of hepatic uricase for conversion of uric acid to allantoin
  
  • Increased serum uric acid leads to increased levels of uric acid and urates within the urine
• Reduced hepatic capacity also reduces the conversion of ammonia to urea
  
  • This is especially prominent in dogs (or cats) with portosystemic vascular anomalies
  • Increased ammonia in the urine
• Ammonia and urates combine to form calculi within the urine, especially at a pH around 6.3

Question 7

Discuss the treatment and management options for dogs and cats with ammonium urate calculi

Answer 7

• Treatment options depend largely on the predisposing causes (eg. Dalmation dog, liver disease) and the clinical signs (eg. urethral obstruction vs asymptomatic)
• Urethral obstruction requires surgery
• If PSVA present, surgical correction can lead to dissolution of the stones
• Infection needs to be controlled - urease producing, urea-splitting bacteria contribute to increased urinary ammonia
• Urine alkalinisation (pH 7.0-7.5) reduces renal tubular ammonia production
• Protein restriction can reduce ammonia production and helps reduce renal medullary urea and concentrating ability ⇒ more dilute urine with less urea/ammonia
• Allopurinol - xanthine oxidase inhibitor - can reduce the production of uric acid
  
  • Must use a purine restricted diet to limit the development of xanthine or hypoxanthine calculi
• Dietary management:
  
  • Purine restircted diet low in calculogenic minerals such as Hills UD

Question 8

List the constellation of products that can be lost in the urine with Fanconi syndrome

Answer 8

• Fanconi syndrome is caused by a proximal tubular defect that results in reduced reabsorption of multiple products
  
  • Glucose
  • Amino acids
  • Protein
  • Phosphate
  • Bicarbonate
  • Sodium
  • Potassium
  • Urate

Question 9

Describe the variable pathogenesis of Fanconi syndrome in dogs and cats

Answer 9

• Genetic and inherited in the Basenji dog (rarely in other breeds)
• Idiopathic
• Aquired following consumption of chicken jerky treats from China
• Secondary to drug administration
  
  • Chlorambucil in cats

Question 10

Describe the pathophysiological consequences and course of disease with genetically acquired Fanconi syndrome

Answer 10

• Onset of signs in affected Basenji’s is ~4-8 years of age
• Glucosuria or isosthenuira occurs first
  
  • Loss of glucose contributes to osmotic diuresis
  • Isosthenuria can develop with concurrent nephrogenic diabetes insipidus (reduced ADH receptors or tubular damage in the distal convoluted tubule)
  • Both of these contribute to polyuria and polydipsia
• Loss of glucose, amino acids and protein in the urine contribute to weight loss and a poor hair coat
• Potassium loss can lead to hypokalaemia which may be associated with muscle weakness
• Bicarbonate loss (and reduced H⁺ secretion) leads to metabolic acidosis
• Sodium loss contributes to hypovolaemia and dehydration
• Progression is variable with renal failure developing over several months while others remain stable for years

Question 11

Discuss the management options for dogs with Fanconi syndrome

Answer 11

• Treatment is supportive and aims to monitor and manage the various metabolic abnormalities that arise

Metabolic acidosis:

• Sodium bicarbonate - no peer-reviewed literature on long term effects
• Potassium citrate (40-75 mg/kg PO q 12 h)
  
  • target and monitor blood bicarbonate and potassium aiming for the normal ranges

Renal Failure:

• Protein restriction
• Fluid therapy as required
• Monitor and manage hypertension
• H2 blockers if required

Note: Long term prognosis is generally good with a median survival time following diagnosis 5.25 years (survey based results)

Question 12

Define the different types of renal tubular acidosis and the underlying causual mechanism

Answer 12

1. Type I RTA
   
   • Distal tubule affected
   • Reduced ability to secrete H⁺
   • Failure of the H⁺K⁺ Antiporter within the alpha intercalated cells in the medullary collecting duct
2. Type II RTA
   
   • Reduced ability of the proximal tubules to reabsorb bicarbonate
   • Defect in the basolateral Na⁺-HCO₃^- co-transporter with leakage of bicarbonate into the tubular lumen
   • Seen as a part of Fanconi syndrome
3. Type IV RTA
   
   • Distal tubules affected
   • Hyperkalaemia results from hypoaldosteronism
   • Reduced aldosterone stimulation of H⁺ATPase

Question 13

Describe the pathophysiology and subsequent clinical features of type I renal tubular acidosis

Answer 13

• Type 1 RTA is caused by a defect in the H⁺K⁺ co-transporter in the distal renal tubule
  
  • Reduced acid secretion into the urine results in an increased urine pH (> 5.3) despite metabolic acidosis
• Increased phosphate secretion (and calciuresis) in the urine
  
  • Can lead to secondary bone disease - osteomalacia - due to phosphorus mobilisation
• Mild hyperkalaemia that can be worsened with alkali therapy

Question 14

Describe the pathophysiology and subsequent clinical features of type II renal tubular acidosis

Answer 14

• Type II RTA is caused by reduced secretion of H⁺ in the distal tubule and collecting duct
  
  • Can occur with reduced function of the H⁺ATPase pump or counter-exchange H⁺K⁺ channel in the type A intercalated cell
• This leads to an inability to produce urine with a pH < 6.0 despite significant metabolic acidosis
• Increased urinary phosphate and calcium loss occurs
  
  • Secondary hyperparathyroidism? and bone loss / osteomalacia
• Hyperchloremia is a consistent feature

Question 15

List the potential causes for nephrogenic diabetes insipidus.

Note the mechanism of cause if known.

Answer 15

1. Congenital
   
   • Deficiency of ADH receptors expressed within the kidney
2. Toxins
   
   • Receptor interference - eg. E. coli endotoxin
3. Drugs
   
   • chemotherapeutics, glucocorticoids
4. Metabolic conditions
   
   • hypokalaemia, hypercalcaemia
5. Tubular injury or loss
   
   • Pyelonephritis, cystic renal disease
6. Medullary washout
   
   • Loss of medullar concentration gradient
   • Increased free water delivery to distal tubule and collecting duct
   • Aquaporin channels cannot accomodate increased water delivery

Question 16

Briefly discuss the treatment options for nephrogenic diabetes insipidus.

Note the mechanism of action for the recommended treatments

Answer 16

Acquired DI

• Treatment for acquired nephrogenic diabetes insipidus is directed at the underlying cause
  
  • Treat infection, stop drugs, balance metabolic conditions

Congential DI

• Protein and sodium restriction
  
  • Reduced solute delivery to the kidney
  • Sodium excretion is relatively constant, therefore reduced sodium intake reduces the need for water and sodium excretion
  • Reduced protein intake ⇒ reduced nitrogenous waste
• Thiazide diuretics
  
  • Block the Na⁺Cl^- transporter in the distal tubule
    
    • Increases sodium loss
  • Stimulates mild dehydration
  • Encourages sodium reuptake in the proximal tubule
    
    • Increases water reabsorption as it follows sodium
  • Aids in a 20-50% reduction in urine output