Calcium oxalate urolithiasis

© August, JR (2006) Consultations in Feline Internal Medicine, Vol 5.  Elsevier Saunders

 

Cats have experienced a dramatic increase in the prevalence of calcium oxalate uroliths since the mid-1980s. Calcium oxalate is the most common mineral component found in feline uroliths, although the mineral component of urethral matrix-crystalline plugs is predominantly struvite. Calcium oxalate uroliths represented less than 5% of feline uroliths before 1987 and rose to 55% by 1999. Although the aetiology of feline urolithiasis is multifactorial, strong evidence suggests that nutritional factors influence disease expression and prevention significantly.

Pathogenesis of stone formation

Calcium oxalate urolithiasis is not a specific disease, but results from underlying disorders that promote precipitation of calcium oxalate in urine. Epidemiological studies have identified numerous genetic, environmental and nutritional factors associated with development of calcium oxalate uroliths. There does not appear to be a direct cause-and-effect scenario.

Urolith formation, dissolution and prevention involve complex physiochemical processes. Major factors include:

  1. urine supersaturation resulting in crystal formation (nucleation)

  2. the effect of inhibitors of mineral nucleation, crystal aggregation and crystal growth

  3. crystalloid complexors

  4. effects of promoters of crystal aggregation and growth

  5. effects of noncrystalline matrix

  6. sufficient urine retention time of slowed transit for the process to occur

The most important driving force behind urolith formation is supersaturation of urine with calculogenic substances, Additionally, urine contains ions and proteins that interact and/or complex with calcium and oxalic acid to allow them to remain in solution. This explains why calcium and oxalic acid in urine normally do not precipitate to form calcium oxalate crystals. Compared with water, urine normally is supersaturated with respect to calcium and oxalic acid. However, energy is required to maintain this state of calcium and oxalic acid solubility, and the maintenance of calcium and oxalic acid in solution remains tenuous. Therefore urine is described as being metastable, which implies varying degrees of instability with respect to the potential for calcium oxalate crystals to form. In this metastable state, new calcium oxalate crystals do not precipitate spontaneously, but if present already, crystals can be maintained and even grow in size. If the concentration of calcium and oxalate is increased, a threshold is eventually reached at which urine cannot hold more calcium and oxalate in solution. The urine concentration at which this occurs is the thermodynamic formation product of calcium oxalate. Above the thermodynamic formation product, urine is oversaturated and unstable with respect to calcium and oxalic acid. Therefore calcium oxalate crystals precipitate spontaneously, grow in size and aggregate. In reality, most calcium oxalate stones form within the metastable region rather than in the region of oversaturation. As saturation increases, protective factors are reduced, or promoters increase, the urine stability declines and crystallization occurs.

Oxalate crystals in urine Xray showing oxalate crystals in bladder

For uroliths that do not dissolve in physiological solutions (such as calcium oxalate), nutritional therapy is designed to prevent further urolith formation or recurrence. The goal is to promote a state of urine undersaturation or reduced saturation to the point of least metastability.

Crystallisation and urolith formation

Once initiation of urolith formation has occurred, the nidus must be retained within the urinary tract and conditions must favour continued precipitation of minerals to promote growth of uroliths. Alterations in balance between urine concentrations of calculogenic substances (calcium and oxalic acid) and crystallisation inhibitors (including citrate, phosphorus, magnesium, sodium and/or potassium) have been associated with initiation and growth of calcium oxalate uroliths. In addition, large molecular weight proteins occurring in urine, such as nephrocalcin, uropontin and Tamm-Horsfall mucoprotein, have an influence on calcium oxalate formation. 

Risk factors

Certain metabolic factors are known to increase risk of calcium oxalate formation in several species, including cats. They include:

  1. Hypercalcaemia - is associated with increased risk of calcium oxalate urolith formation. Hypercalcaemia has been observed in 35% of cats with calcium oxalate uroliths. Conversely, in 20 cats with idiopathic hypercalcaemia, uroliths developed in 35% of the affected cats. When severe, hypercalcaemia results in increased fractional excretion of calcium and hypercalciuria.
  2. Hypercalciuria - is a significant risk factor but not necessarily the cause of calcium oxalate urolith formation in human beings, dogs and cats. Calcium homeostasis is achieved through actions of parathyroid hormone (PTH) and 1,25-dihydroxycholecalciferol (1,25-vitamin D) on bone, intestines and kidneys. When serum ionised calcium concentration decreases, PTH and 1,25-vitamin D activities increase, which results in mobilisation of calcium from bone, increased absorption of calcium from intestine and increased reabsorption of calcium by renal tubules. Factors that alter the activity of these two hormones at any level alter calcium absorption, metabolism and excretion. Hypercalciuria can result from excessive intestinal absorption of calcium (gastrointestinal hyperabsorption), impaired renal reabsorption of calcium (renal leak), and/or excessive skeletal mobilisation of calcium (resorptive). Hypercalciuria in the absence of hypercalcaemia has not been well defined in cats with calcium oxalate uroliths but is thought to occur.
  3. Acidemia - Metabolic acidosis promotes hypercalciuria by promoting bone turnover (release of calcium with buffers from bone), which increases serum ionised calcium concentration and results in increased urinary calcium excretion and decreased renal tubular reabsorption of calcium. Consumption by cats of diets supplemented with the urinary acidifier ammonium chloride has been associated with increased urinary calcium excretion. Additionally, consumption of diets high in animal proteins by human beings results in metabolic acid production and increased urinary calcium excretion.
  4. Aciduria - significant aciduria (pH less than 6.2) may represent a risk factor for calcium oxalate formation because of the associated acidemia and hypercalciuria. In addition, acidic urine alters the function and concentration of some crystallisation inhibitors. Low urine pH decreases urinary citrate concentration by increasing renal proximal tubular citrate reabsorption. Acidic urine is also known to impair the function of macromolecular protein inhibitors.
  5. Inhibitors - inhibitors of crystallisation such as citrate, magnesium, and pyrophosphate form soluble salts with calcium or oxalic acid and thereby reduce the availability of calcium or oxalic acid for precipitation. Other inhibitors, such as Tamm-Horsfall glycoprotein and nephrocalcin, interfere with the ability of calcium and oxalic acid to combine, which thereby minimises crystal formation, aggregation and growth.
  6. Hyperoxaluria - Oxalic acid is a metabolic end-product of ascorbic acid (vitamin C) and several amino acids, such as glycine and serine, derived from dietary sources. Oxalic acid forms soluble salts with sodium and potassium ions but a relatively insoluble salt with calcium ions. Therefore any increased urinary concentration of oxalic acid may promote calcium oxalate formation. Increased dietary intake of oxalate and vitamin B6 deficiency are two known factors that increase urinary oxalate. Hyperoxaluria has been observed experimentally in kittens consuming vitamin-B6-deficient diets, but has not been associated with naturally occurring calcium oxalate urolith formation.
  7. Urine concentration - increasing urine concentration results in increased calcium and oxalic acid saturation and an increased risk for urolith formation. In fact, dilution of urine concentration with a substantial increase in water intake is the mainstay of calcium oxalate prevention in human beings. Cats can achieve urine specific gravities in excess of 1.065, which indicates a marked ability to produce concentrated urine. Many cats affected with calcium oxalate uroliths have a urine specific gravity greater than 1.040, unless some impairment occurs to renal function or concentrating ability.
  8. Calcium oxalate crystalluria - detection of calcium oxalate crystals in sediment indicates that urine is supersaturated with calcium oxalate. Persistent crystalluria reflects an increased risk for calcium oxalate urolith formation. However, calcium oxalate crystalluria is observed in less than 50% of feline cases at time of diagnosis of urolithiasis.

Pharmacological treatment

Occasionally, dietary management is not sufficient to control calcium oxalate crystalluria or urolithiasis. Several pharmacological agents have been used in human beings and dogs and may be beneficial in cats with recurrent or progressive calcium oxalate uroliths.

Citrate - urinary citrate inhibits calcium oxalate crystal formation and is an excellent urinary alkaliser. If an appropriate urinary pH is not achieved by dietary management alone, additional oral potassium citrate may be beneficial. Potassium citrate is administered at a starting dose of 50mg/kg PO q 12hrs. Dosage is titrated by monitoring urine pH, with the target urine pH between 7.0 and 7.5.

Vitamin B6 - - increases transamination of glyoxylate, a precursor of oxalic acid, to glycine. Although experimentally induced vitamin B6 deficiency resulted in renal precipitation of calcium oxalate and hyperoxaluria in kittens, a naturally occurring form of this syndrome has not been observed. Although the ability of supplemental vitamin 6  to reduce urinary oxalic acid excretion in cats with calcium oxalate urolithiasis is unknown, supplementation is inexpensive and safe. It may be considered in cats with calcium oxalate uroliths that are difficult to manage. A dosage of 2-10 mg/kg PO q 24hrs may be used.

Thiazide diuretics - are recommended to reduce recurrence of calcium-containing uroliths in human beings because of their ability to reduce urinary calcium excretion. The exact mechanism(s) by which thiazide diuretics achieve this effect is unknown. Thiazide diuretics directly stimulate distal renal tubular reabsorption of calcium. Although hydrochlorothiazide diuretics may be beneficial in minimising urinary calcium excretion in human beings and dogs (2-4 mg/kg PO q12hrs), these agents have not been evaluated in cats. Side effects associated with this group of drugs include dehydration, hypokalemia and hypercalcaemia; therefore their use cannot be recommended until further studies are performed.

Other agents - Allopurinol has been used to minimise heterogeneous nucleation of calcium oxalate on uric acid crystals; however, this appears to occur rarely in cats. Sodium cellulose phosphate binds calcium in the intestinal tract, limiting its absorption; however, mechanism(s) of calcium oxalate formation including enteric hyperoxaluria in cats is unknown. Orthophosphate may minimise urinary calcium excretion. Glycosaminoglycans may act as urolith inhibitors and help prevent crystal adhesion to the urothelium.