Calcium Oxalate Urolithiasis

Chapter 197


Calcium Oxalate Urolithiasis




Calcium oxalate (CaOx) urolithiasis is a condition affecting dogs and cats that has become more common over the last several decades (Cannon et al, 2007; Low et al, 2010). A recent study examined the composition of uroliths submitted to the Minnesota Urolith Center between the years 1981 and 2007 (Osborne et al, 2008). During this time the percentage of CaOx stones in total submissions increased from 5% to 41% in dogs, whereas that in cats increased from 2% to 41%. Concurrently, the incidence of struvite uroliths decreased from 78% to 40% in dogs and from 78% to 49% in cats. It is thought that the primary factor causing this trend was dietary modifications made to address struvite urolithiasis. Overall, the pathophysiology of CaOx urolithiasis is complex, and much still remains to be understood. This chapter outlines what we know about CaOx urolithiasis and how this knowledge can be applied to design effective therapies for this disease.




Pathophysiology


The physical chemistry governing crystal formation in urine is complex, and many variables must be considered. The two major factors that affect this process are supersaturation of urine with calculogenic materials (calcium and oxalate) and the balance between substances that promote and those that inhibit CaOx formation. When urine is supersaturated with calcium and oxalate, crystal formation is more likely to occur; one measure that reflects this state is the relative supersaturation of urine (RSS). This measure is used widely to assess the risk of CaOx formation in people and is finding use in veterinary medicine as well. In one study, the CaOx RSS of stone-forming dogs was found to be significantly higher than that of control dogs (Stevenson, Robertson et al, 2003).


To assess supersaturation of the urine with calculogenic materials, the relative importance of urinary water content, calcium concentration, and oxalate concentration have been examined. Water content is perhaps the single most important variable affecting CaOx formation. Increased water dilutes the urine and increases urine volume, thereby reducing CaOx RSS. Hyperoxaluria also plays a role. Urinary excretion of oxalate depends on dietary intake, intestinal absorption, renal tubular secretion, and the rate of endogenous synthesis. Intestinal absorption is influenced by factors that determine the amount of free oxalate in the gut lumen. Calcium and magnesium both can bind oxalate, creating complexes that are excreted instead of absorbed. Intestinal flora such as Oxalobacter formigenes and lactic acid bacteria can degrade oxalate and may play a role in the pathophysiology of this disease. Hyperoxaluria due to endogenous overproduction has been found to be a primary genetic condition in people caused by metabolic defects and exists in two forms (type I and type II). A few cases of primary hyperoxaluria also have been reported in cats and appear to be most similar to the type II variant in people (DeLorenzi et al, 2005).


Like oxalate excretion, urinary calcium excretion depends on dietary intake, intestinal absorption, and renal tubular excretion. Intestinal absorption of calcium is similar to that of oxalate in that calcium is poorly absorbed when it exists as a complex but is absorbed more readily when unbound. The appropriate level of calcium intake to minimize urinary CaOx RSS is thus intertwined with the amount of oxalate present, as well as the amount of other substances with which it may form complexes (e.g., phosphate). Hypercalciuria also can result from hypercalcemia, impaired tubular reabsorption of calcium (renal leak), and administration of certain drugs such as glucocorticoids or loop diuretics (e.g., furosemide).


Several substances have been identified as promoting or inhibiting CaOx formation in urine. Inhibitors include magnesium, citrate, and pyrophosphate, which form soluble complexes with calcium in the urine and prevent crystal formation with oxalate. Citrate also may lower the risk of CaOx formation by alkalinizing the urine. Proteins such as nephrocalcin and Tamm-Horsfall glycoprotein interfere with CaOx crystal formation and may play an additional role.


There most likely are many promoters of CaOx formation, but two that have been identified are uric acid and foreign material. Uric acid can block certain CaOx inhibitors, and a group of CaOx-forming miniature schnauzers was found to excrete significantly higher levels of uric acid than healthy controls (Lulich et al, 1991). The presence of foreign material such as intraluminal suture in the urinary tract can act as a nidus for crystal nucleation.


The urinary pH also has been evaluated for its role in CaOx formation, and there is controversy over its importance. The absolute solubility of CaOx in urine is affected marginally over a broad pH range, but there are several reasons why a low pH may promote CaOx formation: persistent aciduria is associated with low-grade metabolic acidosis, which induces calcium resorption from bone and can increase urinary calcium excretion; acidic urine may diminish the ability of citrate and pyrophosphate to act as CaOx inhibitors; and increased reabsorption of calcium from the distal tubule occurs when the urine is alkaline. Furthermore, feeding an acidifying diet has been identified as a risk factor for CaOx formation in cats and dogs. In dogs the risk was three times higher overall (Lekcharoensuk et al, 2002), whereas in cats the risk was three times higher when diets were fed producing a urinary pH of 5.99 to 6.15 compared with diets producing a pH of 6.5 to 6.9 (Lekcharoensuk et al, 2001). Studies also have evaluated the effect of pH specifically on CaOx RSS, but results so far have been conflicting.



Diagnostic Approach


The initial evaluation of a dog or cat with CaOx urolithiasis should include a thorough investigation for any underlying cause. A complete blood count, chemistry panel, urinalysis, and urine culture are considered a minimum database. If the total calcium concentration is elevated, the ionized calcium level should be measured, and if hypercalcemia is confirmed, measurement of parathyroid hormone, parathyroid hormone–related protein, and possibly serum vitamin D levels is recommended. Imaging should include both abdominal radiography and ultrasonography because in some cases stones may be missed when only one modality is used. This is especially the case for ureteroliths, which can cause severe illness. Ultrasonographic imaging also may reveal more detailed information about the urinary tract (e.g., ureteral obstruction, cystitis).



Treatment



Surgical and Interventional Management


There is no known protocol to dissolve CaOx uroliths at this time, and in many cases the only effective treatment is removal. Urolith removal can be achieved surgically, and less invasive methods are becoming increasingly available (see Chapters 195 and 199). Depending on the location of the urolith various techniques may be employed, such as lithotripsy (extracorporeal and intracorporeal), cystoscopic removal, or urohydropulsion. An obstructive stone also can be addressed by the placement of a stent, subcutaneous ureteral bypass device, or other interventional procedures.



Medical Management


Once CaOx urolithiasis is identified, preventive medical management of this problem still is of utmost importance because this is a chronic disease. Dietary options and medications can be used to minimize the chance of stone recurrence or further growth. Additionally, regular monitoring of the patient is needed to evaluate response to therapy and to identify new stones that may form. In the case of a stone in the upper urinary tract (ureterolith, nephrolith), medical strategies are often instituted before surgery or other procedures (see also Chapter 196).



Diet


Perhaps the most important dietary modification that can be made is to increase water intake and urinary volume while decreasing urine specific gravity. Retrospective studies of cats (Lekcharoensuk et al, 2001) and dogs (Lekcharoensuk et al, 2002) with CaOx urolithiasis found a significantly lower risk of CaOx formation with higher dietary moisture content. Feeding a canned diet is the best way to increase water intake, but some dogs and cats will not eat canned food. In these cases, water or broth can be added to dry food, or broth can be added to the water supply. Water fountains also may be helpful to increase water intake in cats. Appropriate targets for specific gravity are less than 1.025 in cats and less than 1.020 in dogs; achieving dilute urine can be very difficult in cats.


Supplementation of sodium chloride has been investigated as a means of increasing water consumption but has been a point of controversy. Increased sodium consumption increases urinary calcium excretion and may increase the risk of CaOx urolithiasis. However, prospective studies have shown that increasing dietary sodium content significantly decreased the CaOx RSS in healthy and CaOx stone–forming dogs (Lulich et al, 2005; Stevenson, Hynds et al, 2003) as well as in healthy cats. The total daily urinary calcium excretion increased in these studies, but apparently the effect on CaOx RSS is offset by the increase in water intake and urine volume. These findings suggest a benefit to NaCl supplementation, but long-term studies still are needed. Sodium supplementation can be considered if there is an inadequate response to dietary therapy and the urine is not dilute, but patient selection must be done carefully. Short-term studies in cats have shown no adverse effects on kidney function or blood pressure, but caution is required when considering adding salt to the diets of dogs or cats with kidney disease or hypertension until longer-term studies are done. Additionally, high-sodium diets are contraindicated for animals with heart disease.


Higher dietary protein historically has been associated with an elevated risk of CaOx formation because it can promote acidosis and hypercalciuria. However, retrospective studies in dogs and cats have found a lower risk of CaOx formation with higher dietary protein (Lekcharoensuk et al, 2001, 2002). Overall, the exact amount and type of protein that is ideal has yet to be determined, but most diets designed to reduce CaOx urolithiasis have reduced protein levels.


The importance of the calcium and oxalate content of food was demonstrated by a study in healthy dogs (Stevenson, Hynds et al, 2003). In these dogs, urinary oxalate excretion and CaOx RSS increased when oxalate intake was increased, but only when the intake of calcium was low. The lowest CaOx RSS was found in dogs fed a diet that was lowest in both calcium and oxalate. If only calcium or only oxalate was decreased, the CaOx RSS increased. This emphasizes the need for a balanced amount of calcium and oxalate in the diet, but in all cases high calcium or oxalate content should be avoided. Examples of high-oxalate foods are leafy green vegetables and nuts. For a more complete list of foods with high oxalate content, see the Oxalosis and Hyperoxaluria Foundation website (www.ohf.org/diet.html).


Vitamin intake also can be important: hypercalciuria can result from excessive vitamin D intake because of enhanced intestinal absorption, and excessive vitamin C may promote hyperoxaluria, although this has yet to be proven in dogs and cats. A deficiency in vitamin B6 (pyridoxine) also may play a role in urinary oxalate excretion. A study in healthy kittens showed that urinary oxalate excretion was higher in those fed a diet deficient in pyridoxine than in those fed a normal amount (Bai et al, 1989). Supplementation with vitamin B6 (2 mg/kg q24-48h PO) thus can be considered as adjunct medical treatment.


Three studies have prospectively evaluated the effect of commercially available urinary diets on dogs and cats with CaOx urolithiasis. The diets evaluated were canned Royal Canin Canine SO Lower Urinary Tract Support, canned Hill’s Prescription Diet Feline c/d-oxl, and canned Hill’s Prescription Diet u/d. A fourth diet is available for cats (Purina Veterinary Diets UR Urinary St/Ox Feline Formula). Unpublished work indicates that feeding this diet to normal cats yielded urine that was metastable for CaOx, which suggests that it would be an appropriate option for cats with CaOx urolithiasis. However, published studies still are needed for a more complete evaluation.


In dogs fed canned Canine SO, the CaOx RSS was reduced significantly by 63% compared to that in dogs fed a maintenance diet (Stevenson et al, 2004). This group of dogs was followed for 12 months, during which time no recurrence of CaOx stones was noted.


In cats fed Prescription Diet Feline c/d-oxl, the activity product ratio (measure of CaOx supersaturation) was reduced significantly by 59% compared with that in the same group of cats fed a variety of dry maintenance diets (Lulich et al, 2004b). This diet is no longer available, but Hill’s Prescription Diet c/d Multicare Feline has similar efficacy according to the manufacturer.


A third study evaluated the effect of feeding canned Prescription Diet u/d to dogs with CaOx urolithiasis (Lulich et al, 2001). Compared with dogs fed a maintenance diet, dogs fed Prescription Diet u/d had significantly lower urinary concentrations of both calcium and oxalate. Protein malnutrition is rare but possible during long-term feeding of Prescription Diet u/d; dogs fed this diet had a significantly lower serum albumin level than controls, although values remained in the normal range. The low protein levels make this diet contraindicated in dogs with dilated cardiomyopathy or in breeds that are predisposed to this disease. In recent years Hill’s has supplemented Prescription Diet u/d with taurine and carnitine, but concerns still remain. In general, veterinary nutritionists recommend against using Prescription Diet u/d as a maintenance diet. Furthermore, this diet tends to be higher in fat and may not be the best choice for dogs with a history of pancreatitis or hyperlipidemia.


As mentioned earlier, acidifying diets have been associated with a higher risk of CaOx formation in both dogs and cats, but further studies have yielded conflicting results regarding the importance of daily urinary pH in CaOx prevention. Overall, it can be said that pH generally appears to be less important in controlling CaOx stone formation than in controlling formation of other stones such as struvite. Given the available information it seems prudent to avoid significant acidification of the urine. An appropriate initial target urine pH is approximately 7.0; however, with this in mind, the target urinary pH values achieved by feeding almost all of the diets listed in Table 197-1 are acidic. The only diet designed to produce a urinary pH of more than 7.0 is Hill’s Prescription Diet u/d, with the others aiming for an acidic pH. This is because the goal of the Royal Canin Urinary SO formulation and Hill’s Prescription Diet c/d Multicare is to prevent both CaOx and struvite uroliths. Since urine pH control is more important for dissolution and prevention in treating struvite stones than in treating CaOx stones, these diets target a lower pH as part of the strategy to prevent struvites. Despite causing a mildly acidic urine, all the listed diets are effective in producing urine with a low CaOx RSS. This apparent paradox exemplifies the complex nature of CaOx urolithiasis and the many factors must be considered in designing an appropriate diet. Of course, if CaOx uroliths continue to be a problem despite feeding an appropriate diet, alkalinization of the urine can be considered (see later) to potentially improve control.


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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Calcium Oxalate Urolithiasis
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