Published in IVIS with the permission of the editor Close window to return to IVIS ROYAL CANIN VIEWPOINT Urine dilution: a key factor in the prevention of struvite and calcium oxalate uroliths KEY POINTS The easiest way of reducing supersaturation in urine, and thus the risks of crystal formation, is to increase urine volume Vincent Biourge, DVM, PhD, Dipl. ACVN, Dipl. ECVCN Royal Canin, Research Center, Aimargues, France Dr. Biourge graduated from the Faculty of Veterinary Medicine of the University of Liège (Belgium) in 1985. He remained as an assistant in the Department of Nutrition for 2 years before moving to the Veterinary Hospital at University of Pennsylvania (Philadelphia, USA) and later to the Veterinary Medical Teaching Hospital of the University of California (Davis, USA). In 1993, he was awarded a PhD in Nutrition from the University of California and he became a Diplomate of the American College of Veterinary Nutrition. In 1994, he joined the Research Center of Royal Canin in Aimargues (France) as Head of Scientific Communication and Nutritionist. Since January 1999, Dr. Biourge has been in charge of managing the nutritional research program of Royal Canin. Increased dietary sodium chloride (NaCl) increases water intake as well as urine ion and decreases urine supersaturation A single acidifying diet moderately supplemented with NaCl can be formulated for the prevention of both struvite and calcium oxalate uroliths as well as for the dissolution of struvite stones Urinary ph, struvite and calcium oxalate The finding in the mid 8 s that an alkaline urinary ph (ph > 6.5) was the main factor in the pathophysiology of struvite crystals and stones prompted the industry to re-formulate their diets (1,2). According to experts, the generalization of those socalled "acidifying-diets" appears to have induced a dramatic decrease in the prevalence of cats presented at veterinary clinics with signs of urethral obstruction (1). It also prompted a debate within the veterinary community about the potential health risks associated with over-acidification (2). The fact is that the pathophysiology of CaOx uroliths is still poorly understood and that the association with acidifying diets might be due to other confounding factors such as the increased lifespan of pets, as well as the other formulation changes in petfoods that occurred over the same period (3). Moreover this association does not hold for dogs where acidifying diets are much less common. Vol 17 No 1 / / 7 / / Veterinary Focus / / 41
ROYAL CANIN VIEWPOINT Figure 1. Regions of relative supersaturation (RSS). (modified from 7) Contrary to struvite crystals, calcium oxalate (CaOx) crystals have a very poor solubility. For CaOx, it is almost impossible to obtain a RSS value below 1. RSS CaOx 12 Struvite 2.5 LABILE SUPERSATURATION Spontaneous crystallization Rapid crystal growth Formation METASTABLE SUPERSATURATION No crystal dissolution No spontaneous crystallization Solubility UNDERSATURATION No crystallization Crystal dissolution Based on epidemiological studies linking the acidifying potential of diets to the risks of forming CaOx stones, today s leading opinion is that urinary ph is the most important factor for preventing the recurrence of CaOx uroliths (4). Based on this theory, it is impossible to formulate a diet that will both prevent the formation of struvite and CaOx, as the former requires to induce a low and the latter, a high urinary ph. Urinary ph and relative supersaturation Urinary ph alone does not allow us to evaluate the risk of forming CaOx crystals in the urinary tract. A much better tool is the urinary relative supersaturation (RSS). It is the most widely used method in humans and has been validated for dog and cat urine (5). (See article from B. Robertson and A. Stevenson on page 37). The formation, growth and dissolution of urinary crystals depends on the concentrations of the minerals that make the crystal (i.e.: calcium and oxalate) that are free to react with each other (5). It is possible to calculate those free fractions of calcium and oxalate. The of the concentrations of those free fractions is called the activity. The RSS for a given salt is defined as the ratio of the activity divided by the thermodynamic solubility for that salt. RSS CaOx can be dissolved in a solvent (i.e. water), for a given temperature (i.e. 37 C) and a given ph (i.e. 6.). - An RSS <1 means that the urine is undersatured and that crystals will not form but will dissolve (Figure 1). - An RSS> 1 means that the urine is supersaturated and that crystals might form but will not dissolve. In a complex media such as urine, it is possible to have a RSS for CaOx or struvite above 1 without spontaneous precipitation of crystals (6). This level of supersaturation is qualified as metastable supersaturation (Figure 1). At this level of saturation, CaOx crystals will not form spontaneously but might occur in the presence of a nucleus. At higher levels of minerals in the urine, crystals will form spontaneously within minutes to hours. This is the labile supersaturation (Figure 1). The limit between metastable and labile supersaturation is called the formation. Kinetic precipitation studies in urine have shown that the RSS for the formation is 2.5 for struvite and 12 for CaOx. Calculation of RSS from the urine of cats or dogs fed a specific diet can be used to study the effect of that diet on the crystallization potential of urine (5,6). Both commercial and experimental diets have been evaluated by this mean in our facility, at the WALTHAM Centre for Pet Nutrition and by other investigators. As expected those studies have shown that feline and canine diets can be formulated to induce undersaturated (RSS <1) urine for struvite and that the main drivers are ph Individual data on 125 diets Dry food Wet food Formation Solubility 5 5.5 6 6.5 7 7.5 8 8.5 Low CaOx RSS despite low ph Urinary ph The thermodynamic solubility is the maximum amount of a given salt that Figure 2. Relationship between urinary ph and calcium oxalate (CaOx) crystals in healthy cats. 42 / / Veterinary Focus / / Vol 17 No 1 / / 7
URINE DILUTION: A KEY FACTOR IN THE PREVENTION OF STRUVITE AND CALCIUM OXALATE UROLITHS and/or dietary moisture. On all diets, urine from healthy dogs and cats is close to saturation or supersaturated for CaOx (RSS 1) (Figure 2). However, CaOx RSS are below the formation (RSS CaOx=12) and spontaneous crystallization is not observed. When comparing urinary ph and CaOx RSS values associated with various commercial and experimental feline diets, urinary ph appears to be a very poor predictor of CaOx RSS (Figure 2). These findings strongly suggest that relying on urine ph alone to formulate diets does not allow us to predict their effects on urine CaOx crystallization potential! The use of RSS as a tool to evaluate the urine crystallization potential has also allowed interesting findings. For example, the urine of small dogs is more saturated than the urine of large dogs (7) (Figure 3). This would explain the higher incidence of urinary stones in small than large breeds. Stoneforming dogs have a significantly higher CaOx RSS than healthy dogs, suggesting that RSS might be a good tool to identify stone formers in dogs (3). Dietary sodium, dietary moisture and relative supersaturation Dietary sodium (or sodium chloride) and dietary moisture are highly effective in stimulating water consumption and diuresis in dogs and cats (8). Increased diuresis will promote urine dilution and thus decrease the concentration of poorly soluble minerals. Increased urine volume will also promote urine flow and the rate of micturition, providing insufficient time for the nucleation and aggregation of urine crystals (7). Work in our facility and published studies in both dogs and cats have shown that increased dietary sodium (.7 to 1.3 g/ 4 kcal metabolizable energy), high dietary moisture or both were valuable tools to reduce CaOx RSS (8,-12) (Figures 3 and 4). A prospective study, evaluating the efficacy of a diet designed for the prevention of both struvite (thus acidifying) and CaOx uroliths, found that increased moisture and sodium reduced the urine crystallization potential of stone-forming dogs (3). Moreover, none of those dogs relapsed over a one-year follow-up (3). This suggests that diets that reduce CaOx RSS in healthy dogs are also effective in dogs suffering from CaOx uroliths. Increased moisture intake has also been shown to reduce CaOx RSS in stone former cats (12). Epidemiological studies on dietary factors and the prevalence of CaOx stones in cats, as well as in dogs, concluded similarly on the benefits of dietary sodium and moisture (2,13,14). Dietary sodium and calcium excretion The link between dietary Na and urinary Ca excretion led to the assumption that high salt diets Calcium oxalate RSS 15 5 Influence of breed and dietary moisture on CaOx RSS Labrador Retriever Miniature Schnauzer Labrador Retriever Miniature Schnauzer Breed Breed These graphs illustrate 3 factors that will affect CaOx RSS: - Breed: fed the same diet, small breed dogs (such as Miniature Schnauzers) will produce a more saturated urine for CaOx (CaOx RSS is higher) than large breed dogs (such as Labrador Retriever). This might explain in part why small breed dogs are more prone to CaOx uroliths than large breed dogs. - Dietary moisture: a high moisture content tends to induce a lower RSS. This difference is significant for the Miniature Schnauzer. - Dietary sodium: CaOx RSS drops significantly when dietary sodium content increases. In Miniature Schnauzers, a moderate sodium content (1.2%) has a more dramatic effect than increasing moisture to 73%. Figure 3. Influence of breed, dietary moisture and dietary sodium on CaOx RSS. Calcium oxalate RSS Influence of breed and dietary sodium on CaOx RSS 8 Labrador Retrievers and 8 Miniature Schnauzers were included in the study, number with a different superscript are significantly different 25 11.28 13.87 ab 9.83 13.21 8.5 a 15 8.97 a 9.13 ab Dry food 5.42 ab (7% moisture) 3.62 b 5.73 b Canned food 5 (73% moisture).5 g/ kcal (i.e..2% in a 4 kcal/kg food). g/ kcal (i.e..8% in a 4 kcal/kg food).3 g/ kcal (i.e. 1.2% in a 4 kcal /kg food) Vol 17 No 1 / / 7 / / Veterinary Focus / / 43
URINE DILUTION: A KEY FACTOR IN THE PREVENTION OF STRUVITE AND CALCIUM OXALATE UROLITHS Figure 4. Relationship between dietary sodium and calcium oxalate (CaOx) relative supersaturation. the concomitant increase in urine volume and so a significant decrease in CaOx RSS is observed (11). RSS CaOx Na <.5% Na >.5% 18 16 14 12 8 6 4 2 Dry food Wet food Formation Solubility...4.6.8 1. 1. 1.4 1.6 1.8 2. Dietary Na (% DM) could promote calcium oxalate formation in both dogs and cats, and thus to the recommendation that diets designed for the management of LUTD should be low in Na (1,11). However, increased sodium intake increases calcium excretion but calcium concentration does not increase because of Conclusion RSS has already proven to be a valuable tool to study the effect of dietary factors on urine saturation in cats. However, more work will be necessary to understand CaOx urolith pathophysiology, individual variations and breed specificities as well as to find other strategies to affect urine mineral concentrations. Our findings and published studies strongly suggest that increasing dietary moisture and/or NaCl in an acidifying diet will reduce the risks of forming both CaOx and struvite crystals (3,7,-12). To date no published data supports that this dietary strategy could be harmful to healthy cats (i.e. showing no clinical signs). REFERENCES 1. Osborne CA, Kruger JM, Lulich JP, et al. Feline Lower Urinary Tract Diseases. In: Ettinger S & Feldman E (eds). Textbook of Veterinary Internal medicine. WB Saunders, Philadelphia, pp 17-1746. 2. Kirk CA, Ling GV, Franti CE, et al. Evaluation of factors associated with development of calcium oxalate urolithiasis in cats. J Am Vet Med Assoc 1995; 7:1429-1434. 3. Stevenson AE, Blackburn JM, Markwell PJ, et al. Nutrient intake and urine composition in calcium oxalate stone-forming dogs: comparison with healthy dogs and impact of dietary modification. Vet Ther 4; 5: 218-231. 4. Bartges JW, C Kirk, IF Lane. Update: management of calcium oxalate uroliths in dogs and cats. Vet Clin North Am Small Anim Pract 4; 34: 969-987. 5. Robertson WG, Jones JS, Heaton MA, et al. Predicting the crystallisation potential of urine from cats and dogs with respect to calcium oxalate and magnesium ammonium phosphate (struvite). J Nutr 2; 132: 1637s- 1641s. 6. Markwell PJ, Smith BHE, McCarthy KP. A non-invasive method for assessing the effect of diet on urinary calcium oxalate and struvite relative supersaturation in the cat. Animal Technology 1999; 5: 61-67. 7. Stevenson AE, Markwell P. A comparison of urine parameters produced by healthy Labradors and Miniature Schnauzers. Am J Vet Res 1; 62: 1782-1786. 8. Burger I, Anderson RS, Holme DW. Nutritional factors affecting water balance in dog and cat. In: Anderson RS (ed). Nutrition of the Cat and Dog. Pergamon Press, Oxford 198, pp. 145-156. 9. Biourge V, Devois C, Morice G, et al. Increased Dietary NaCl significantly increases urine volume but does not increase urinary calcium oxalate supersaturation in healthy cats. Proceedings of the 19th American Congress of Veterinary Internal Medicine, Denver, Colorado, 1, pp. 866.. Hawthorne AJ, Markwell PJ. Dietary sodium promotes increased water intake and urine volume in cats. J Nutr 4; 134: 2128s-2129s. 11. Lulich JP, Osborne CA, Sanderson SL. Effects of dietary supplementation with sodium chloride on urinary relative supersaturation with calcium oxalate in healthy dogs. Am J Vet Res 5; 66: 319-324. 12. Lulich JP, Osborne CA, Lekcharoensuk C, et al. Effects of diet on urine composition of cats with calcium oxalate urolithiasis. J Am Anim Hosp Assoc 4; 4: 185-191. 13. Lekcharoensuk C, Osborne CA, Lulich JP, et al. Association between dietary factors and calcium oxalate and magnesium phosphate urolithiasis in cats. J Am Vet Med Assoc 1; 219:1228-1237. 14. Lekcharoensuk C, Osborne CA, Lulich JP, et al. Associations between dry dietary factors and canine calcium oxalate. Am J Vet Res 2; 63:33-337. 44 / / Veterinary Focus / / Vol 17 No 1 / / 7