Influence of nutrition on feline calcium oxalate urolithiasis with emphasis on endogenous oxalate synthesis

The prevalence of calcium oxalate (CaOx) uroliths detected in cats with lower urinary tract disease has shown a sharp increase over the last decades with a concomitant reciprocal decrease in the occurrence of struvite (magnesium ammonium phosphate) uroliths. CaOx stone-preventative diets are available nowadays, but seem to be marginally effective, as CaOx urolith recurrence occurs in patients fed these diets. In order to improve the preventative measures against CaOx urolithiasis, it is important to understand its aetiopathogenesis. The main research focus in CaOx formation in cats has been on the role of Ca, whereas little research effort has been directed towards the role and origin of urinary oxalates. As in man, the exogenous origin of urinary oxalates in cats is thought to be of minor importance, although the precise contribution of dietary oxalates remains unclear. The generally accepted dietary risk factors for CaOx urolithiasis in cats are discussed and a model for the biosynthetic pathways of oxalate in feline liver is provided. Alanine:glyoxylate aminotransferase 1 (AGT1) in endogenous oxalate metabolism is a liver-specific enzyme targeted in the mitochondria in cats, and allows for efficient conversion of glyoxylate to glycine when fed a carnivorous diet. The low peroxisomal activity of AGT1 in cat liver is compatible with the view that felids utilised a low-carbohydrate diet throughout evolution. Future research should focus on understanding de novo biosynthesis of oxalate in cats and their adaptation(s) in oxalate metabolism, and on dietary oxalate intake and absorption by cats

Nutrition and oxalate metabolism in cats

Over the past 30 years, a progressive increase in calcium oxalate (CaOx) urolith prevalence is reported in cats and dogs diagnosed with urolithiasis. This increase in prevalence appears to have occurred since dietary modifications were introduced to address magnesium ammonium phosphate urolithiasis. Therefore, the main objective of this thesis was to provide information on the role of nutrition in the formation of CaOx uroliths in carnivores with emphasis on the influence of diet on urinary oxalate excretion. This objective was reached by conducting the following studies: Following a short general introduction (Chapter 1), the generally accepted dietary risk factors for CaOx urolithiasis were discussed in a literature review (Chapter 2). For one of the risk factors, i.e. oxalate, it was hypothesized that a high carbohydrate intake by today’s feline diet may induce the biosynthesis of oxalate. An epidemiologic study was carried out to obtain more information on the range of urinary oxalate and calcium excretion in CaOx-forming patients (Chapter 3b) and in healthy dogs and cats (Chapter 3a). Within a sample of the (healthy) Dutch dog and cat population, the range in urinary oxalate and calcium excretion was broad and changes in these values were associated with both dietary and animal-related factors including feeding of a raw meat vs. a dry (extruded) diet (Chapter 3a). Hypercalciuria rather than hyperoxaluria appeared to be a predisposing factor for CaOx urolith formation in individual dogs and cats (Chapter 3b). To obtain more detailed information on the relationship between dietary composition and urinary oxalate excretion, a retrospective cohort study was carried out by the use of a large (and unique) data set containing the exact nutrient intake and urinary oxalate excretions by cats kept under controlled conditions (Chapter 4). Intake of nutrients related to intestinal dietary oxalate absorption and endogenous oxalate synthesis were both associated with changes in urinary oxalate excretion; however, a considerable part of the variation was associated with other factors which were not included in the model used. A randomized controlled trial with cats was carried out to research the effect of changes in macronutrient profile on the excretion of endogenous oxalate (Chapter 5). In these cats, dietary macronutrient profile, when corn starch and sucrose were used as the carbohydrate source and casein as the protein source, did not appear to affect endogenous oxalate excretion. In another randomized controlled trial with cats, the effect of dietary hydroxyproline on urinary excretion of endogenous oxalate, as well as the effect of dietary oxalate on exogenous urinary oxalate, was researched (Chapter 6). In these cats, increases in dietary hydroxyproline, but not dietary oxalate intake, were able to increase urinary oxalate excretion. In the last chapter (Chapter 7) an overview of the obtained results, a general discussion and recommendations for future research were provided. Since the contribution of exogenous oxalate to urinary oxalate excretion is likely to be low, it is advised for future studies to focus on reducing endogenous oxalate excretio

Changes in dietary macronutrient profile do not appear to affect endogenous urinary oxalate excretion in healthy adult cats

The progressive increase in calcium oxalate uroliths reported in cats diagnosed with urolithiasis may partly be due to changes in nutrition. Since cats have a predominant mitochondrial alanine:glyoxylate aminotransferase 1 (AGT1) location, high carbohydrate intake may induce endogenous oxalate synthesis. This hypothesis was tested by feeding 12 adult, female cats three diets differing in macronutrients, namely, high protein (HP), high carbohydrate (HC) and high fat (HF), using a randomised Latin square design in a 36-day study. In addition to plasma, urine was collected quantitatively using modified litter boxes. A pilot study with four cats, conducted to determine the adaptation time of urinary oxalate (Uox) excretion to a dietary change, indicated a mean (±SEM) adaptation time of 5.9 ± 0.7 days, with the urinary oxalate:creatinine (Ox:Cr) ratio increasing from 36.1 ± 3.7 to 81.6 ± 2.3 mmol/mol. In the main study, plasma oxalate concentration was significantly lower when feeding the HP compared to the HF (P = 0.003) diet, whereas Uox excretion (µmol/kg BW0.75/day) and the urinary Ox:Cr ratio were unaffected by diet. The Uox concentration (mmol/L) was significantly lower when feeding the HP compared to the HC (P = 0.004) and HF (P = 0.001) diets. The results indicate that changes in macronutrient profile may not influence endogenous Uox excretion in cats but high dietary protein did reduce Uox concentration and may therefore help to lower the risk of calcium oxalate formation

Short communication: Urinary oxalate and calcium excretion by dogs and cats diagnosed with calcium oxalate urolithiasis

Introduction Urine concentrations of oxalate and calcium play an important role in calcium oxalate (CaOx) urolith formation in dogs and cats, with high excretions of both substances increasing the chance of CaOx urolithiasis. In 17 CaOx-forming dogs, urine calcium:creatinine ratio (Ca:Cr) was found to be increased compared with healthy control dogs, whereas urine oxalate:creatinine ratio (Ox:Cr) did not differ (Stevenson and others 2004). In six CaOx-forming miniature schnauzers, urinary calcium excretion (in mg/kg/24 hours) was increased compared with healthy controls, while urinary oxalate excretion was not affected (Lulich and others 1991). However, in these studies, the urine samples were not always collected at the time CaOx uroliths were actually present in the urinary tract. Moreover, in these studies, individual urinary oxalate and calcium excretions were mostly not provided. The objective of this study was to determine the urinary oxalate and calcium excretion rates, and the urinary calcium to oxalate ratio (Ca:oxalate), at the time CaOx uroliths were present in the urinary tract of dogs and cats. Materials and Methods Data for this observational study were collected through urine sampling and questionnaires from May 2010 to January 2012. Participation in this study was voluntary, and informed consent was obtained from dog and cat owners who consulted the University Clinic for Companion Animals of the Utrecht University because of urolithiasis. Dogs and

Influence of nutrition on feline calcium oxalate urolithiasis with emphasis on endogenous oxalate synthesis

The prevalence of calcium oxalate (CaOx) uroliths detected in cats with lower urinary tract disease has shown a sharp increase over the last decades with a concomitant reciprocal decrease in the occurrence of struvite (magnesium ammonium phosphate) uroliths. CaOx stone-preventative diets are available nowadays, but seem to be marginally effective, as CaOx urolith recurrence occurs in patients fed these diets. In order to improve the preventative measures against CaOx urolithiasis, it is important to understand its aetiopathogenesis. The main research focus in CaOx formation in cats has been on the role of Ca, whereas little research effort has been directed towards the role and origin of urinary oxalates. As in man, the exogenous origin of urinary oxalates in cats is thought to be of minor importance, although the precise contribution of dietary oxalates remains unclear. The generally accepted dietary risk factors for CaOx urolithiasis in cats are discussed and a model for the biosynthetic pathways of oxalate in feline liver is provided. Alanine:glyoxylate aminotransferase 1 (AGT1) in endogenous oxalate metabolism is a liver-specific enzyme targeted in the mitochondria in cats, and allows for efficient conversion of glyoxylate to glycine when fed a carnivorous diet. The low peroxisomal activity of AGT1 in cat liver is compatible with the view that felids utilised a low-carbohydrate diet throughout evolution. Future research should focus on understanding de novo biosynthesis of oxalate in cats and their adaptation(s) in oxalate metabolism, and on dietary oxalate intake and absorption by cats

The effect of dietary hydroxyproline and dietary oxalate on urinary oxalate excretion in cats

In humans and rodents, dietary hydroxyproline (hyp) and oxalate intake affect urinary oxalate (Uox) excretion. Whether Uox excretion occurs in cats was tested by feeding diets containing low oxalate (13 mg/100g DM) with high (Hhyp-Lox), moderate (Mhyp-Lox), and low hyp (Lhyp-Lox) concentrations (3.8, 2.0 and 0.2 g/100g DM, respectively), and low hyp with high oxalate (93 mg/100g DM; Lhyp-Hox) to 8 adult, female cats in a 48-d study using a Latin square design. Cats were randomly allocated to 1 of the four 12-d treatment periods and fed according to individual energy needs. Feces and urine were collected quantitatively using modified litter boxes during the final 5 d of each period. Feces were analyzed for oxalate and Ca, and urine for specific density, pH, oxalate, Ca, P, Mg, Na, K, ammonia, citrate, urate, sulphate, and creatinine. Increasing hyp intake (0.2, 2.0, and 3.8 g/100g DM) resulted in increased Uox excretion (Lhyp-Lox vs. Mhyp-Lox vs. Hhyp-Lox, P <0.05), and the linear dose-response equation was: Uox (mg ¿d(-1)) = 5.62 + 2.10 x g hyp intake/d (r(2) = 0.56; P <0.001). Increasing oxalate intake from 13 to 93 mg/100g DM did not affect Uox excretion, but resulted in an increase in fecal oxalate output (P <0.001) and positive oxalate balance (32.20 ± 2.06 mg¿d(-1)). The results indicate that the intestinal absorption of the supplemental oxalate, and thereby its contribution to Uox, was low (5.90 ± 5.24%). Relevant increases in endogenous Uox excretion were achieved by increasing dietary hyp intake. The hyp-containing protein sources should be minimized in Ca ox urolith preventative diets until their effect on Uox excretion is tested. The oxalate content (up to 93 mg/100g DM) in a diet with moderate Ca content does not contribute to Uox content

Dietary and animal-related factors associated with the rate of urinary oxalate and calcium excretion in dogs and cats

This paper reports the results of a cohort study and randomised clinical trial (RCT) in cross-over design. In the cohort study, the range of urinary oxalate (Uox) and calcium (Uca) excretion was determined within a sample of the Dutch population of dogs and cats, and dietary and animal-related factors associated with these urine parameters were identified. Spot urine samples were collected from privately owned dogs (n=141) and cats (n=50). The RCT determined the effect of a commercial raw meat diet versus a dry diet on Uox and Uca excretion rate in 23 dogs. In the cohort study, Uox excretion ranged from 21.1 to 170.6 mmol oxalate/mol creatinine in dogs and 27.5 to 161.6 in cats. Urinary calcium excretion ranged from 3.4 to 462.8 mmol calcium/mol creatinine in dogs and 10.1 to 128.0 in cats. In dogs, increased Uox and Uca excretion was associated with (1) the intake of a dry diet as the primary source of energy, (2) receiving no snacks and (3) breed. Increased Uox excretion was associated with males as well. In cats, urine collection in anaesthetised subjects was identified as a confounder. In the RCT, feeding the dry diet resulted in higher Uox (