Sodium in feline nutrition

Transcription

1 DOI: /jpn REVIEW ARTICLE Sodium in feline nutrition P. Nguyen 1, *, B. Reynolds 2, *, J. Zentek 3, N. Paßlack 3 and V. Leray 1 1 Nutrition and Endocrinology Unit, LUNAM Universite, Oniris, National College of Veterinary Medicine, Food Science and Engineering, Nantes, France 2 Clinical Research Unit, University of Toulouse, INP, National Veterinary School of Toulouse, Toulouse, France, and 3 Institute of Animal Nutrition, Department of Veterinary Medicine, Freie Universit at Berlin, Berlin, Germany Summary High sodium levels in cat food have been controversial for a long time. Nonetheless, high sodium levels are used to enhance water intake and urine volume, with the main objective of reducing the risk of urolithiasis. This article is a review of current evidence of the putative risks and benefits of high dietary sodium levels. Its secondary aim is to report a possible safe upper limit (SUL) for sodium intake. The first part of the manuscript is dedicated to sodium physiology, with a focus on the mechanisms of sodium homeostasis. In this respect, there is only few information regarding possible interactions with other minerals. Next, the authors address how sodium intake affects sodium balance; knowledge of these effects is critical to establish recommendations for sodium feed content. The authors then review the consequences of changes in sodium intake on feline health, including urolithiasis, blood pressure changes, cardiovascular alterations and kidney disease. According to recent, long-term studies, there is no evidence of any deleterious effect of dietary sodium levels as high as 740 mg/mj metabolizable energy, which can therefore be considered the SUL based on current knowledge. Keywords sodium, salt, urolithiasis, renal, cardiac, cats Correspondence P. Nguyen, Nutrition and Endocrinology Unit, Oniris, National College of Veterinary Medicine, Food Science and Engineering, C.S , Nantes Cedex 3, France. Tel: ; Fax: ; patrick.nguyen@oniris-nantes.fr This review was prepared by a working group of the Scientific Advisory Board of the FEDIAF (Federation des Industries des Aliments pour Animaux Familiers European Pet Food Industry Federation). The working group was composed of H. Seyffarth, I. Van Hoek, J. Debraekeleer, P. Nguyen, J. Nordholm and J. Zentek. *Authors made equal contribution. Received: 18 December 2014; accepted: 9 May 2016 Introduction Sodium levels in cat food have been and still are a controversial issue in veterinary science. Some commercial diets modify sodium contents for the therapeutic management of some pathologies [especially urolithiasis (higher sodium content), kidney failure and cardiac problems (lower sodium levels)]; however, the relationship between sodium intake and health problems in human medicine has led to doubts and concerns about the high sodium levels in cat food. Until recently, the role of sodium in feline nutrition (especially high dietary levels) and the associated implications for cat health and disease were unclear, the main reason for the controversy. Recent scientific reports have shed new light on the debate. The primary aim of this work is to review current evidence regarding dietary sodium levels and their potential benefits, risks and safety in feline nutrition. Its secondary aim is to report a possible safe upper limit (SUL) for sodium intake, based on current knowledge. Sodium physiology Body functions of sodium Potassium, chloride and sodium are the principal electrolytes of body fluids. The sodium content of adult mammals is approximately 0.13% of body weight (BW) (National Research Council (NRC), 2006). Kienzle et al. (1991) reported total body sodium concentrations of 1.9 g/kg BW in kittens and 1.4 g/kg BW in adult cats. Approximately one-third of the body s sodium is sequestered in the integral structure of the skeleton and is therefore not available for exchange with fluid compartments (Rose, 2010). The remainder occurs mainly in the interstitial fluid (29%), in blood plasma (12%) and to a lesser extent in collagenous tissues and as an intracellular ion (Sheng, 2013). Sodium and chloride are the major Journal of Animal Physiology and Animal Nutrition 101 (2017) Blackwell Verlag GmbH 403

2 Sodium in feline nutrition P. Nguyen et al. electrolytes found predominantly in the extracellular fluid, whereas potassium is located mainly inside the cell. The concentration of sodium ions in the extracellular fluid, and thus in the plasma, is maintained within narrow limits: approximately 155 meq/l in domestic cats (DiBartola, 2000). Sodium has complex physiological and biochemical functions because it determines and maintains the ionic and osmotic balances between the intra- and extracellular fluids, triggering electrical potential in excitable tissues and underlying nerve impulse generation and transmission. Transmembrane potential difference is caused by the differential electrical and chemical gradients of sodium and potassium across cell membranes, which are established by the Na-K pump (Sheng, 2013). Any change in plasma sodium concentration alters plasma osmolarity or tonicity and triggers physiological regulatory mechanisms to adjust water intake and water excretion in order to restore osmolarity to normal levels. Mechanisms of sodium homeostasis The kidney is widely implicated in sodium regulation in the body. Approximately 95% of plasma sodium is filtered at the initial part of the nephron; major sodium homeostasis mechanisms modulate its reabsorption rates in the distal nephron (Hall, 2011a,c). Three major mechanisms participate in the regulation of sodium balance (Fig. 1). The first major mechanism involves vascular pressure receptors and their efferent renal sympathetic and arginine vasopressin pathways. Vascular pressure receptors (baroreceptors) are present in several sites in the vascular bed; they detect changes in circulating blood volume and pressure and send impulses to the central nervous system. When the central nervous system receives hypervolaemic signals from baroreceptors, the secretion of the hormone arginine vasopressin, which increases plasma volume, is inhibited; conversely, its secretion is stimulated when hypovolaemia occurs (Hall, 2011a). In hypovolaemic states, arginine vasopressin allows the body to conserve water and sodium by stimulating water reabsorption in the kidneys, which also enhances sodium renal reabsorption. At the same time, decreases in systemic arterial pressure stimulate renal sympathetic innervation, reducing the urinary excretion of sodium by reducing renal blood flow and glomerular filtration rate (GFR), increasing reabsorption of sodium and chloride, and stimulating renin release (Hall, 2011a). The second major mechanism of sodium homeostasis is the renin angiotensin aldosterone system (RAAS). Renin is released as a consequence of hypovolaemia and activates angiotensinogen to angiotensin I, which is released by the liver into the circulation and converted by angiotensin-converting enzyme (ACE). The active form of angiotensin (angiotensin II) causes arteriolar constriction, stimulates arginine vasopressin release and increases thirst sensation. Furthermore, angiotensin II conserves body sodium by reducing its urinary excretion and by stimulating aldosterone secretion. In addition to angiotensin II, low plasma sodium concentrations and high plasma potassium concentrations also stimulate aldosterone secretion by the adrenal cortex. In the kidney, aldosterone stimulates sodium reabsorption and potassium secretion (Hall, 2011a,b,c). Natriuretic peptides comprise the third major mechanism of sodium homeostasis. In contrast to the effects of the two mechanisms described above, natriuretic peptides exert potent natriuretic, diuretic and vasodilative effects and are secreted during hypervolaemia (Levin et al., 1998). Their effects include the inhibition of aldosterone secretion and the promotion of sodium excretion by the kidneys (by increasing the GFR, inhibiting sodium reabsorption in nephrons and inhibiting arginine vasopressin secretion) (Hall, 2011c). Appetite for sodium Sodium (or salt) appetite describes the behaviours of animals that seek or choose sodium solutions over water, or salted over unsalted food, notably when they need sodium. Evidence for sodium appetite has been found in a wide variety of herbivorous and omnivorous species (Geerling and Loewy, 2008). However, studies in dogs (Rowland and Fregly, 1988) and cats (Yu et al., 1997) uncovered no sodium preferences in normal conditions or in sodium-depleted animals. Yu et al. (1997) reported that 24 kittens had neither an innate nor a sodium deficiency-induced salt appetite and that their sodium status had no effect on their choice of diets containing various levels of sodium. Sodium balance and dietary requirements Absorption of dietary sodium Sodium absorption happens in cells of the upper small intestine, mainly through cotransport with glucose and amino acids; however, data in dogs suggest colonic absorption of sodium as well (Hill et al., 2001). Absorbed sodium is rapidly exported from the cell via 404 Journal of Animal Physiology and Animal Nutrition 101 (2017) Blackwell Verlag GmbH

3 P. Nguyen et al. Sodium in feline nutrition Vessels baroreceptors Sensitive to volemia changes Afferent pathways Central Nervous System Efferent pathways Angiotensinogen Angiotensin I Renin Kidney Sodium reaborption in tubules AVP Aldosterone Natriuretic peptides Angiotensin II Fig. 1 Summary of the mechanisms of sodium regulation. Solid lines represent stimulation and dashed lines represent inhibition of the release of the hormones related to sodium homeostasis, of peripheral and central nervous pathways, and renal sodium reabsorption. [Colour figure can be viewed at wileyonlinelibrary.com] sodium pumps and then diffuses into capillary blood within the villus. Apparent sodium absorption was measured in domestic cats by Yu and Morris (1997), with values of 45 86% (mean 74.5%) in growing kittens ingesting different levels of dietary sodium [ g/kg ( mg/mj metabolizable energy (ME), assuming 16-MJ ME/kg diets)]. Similarly, in adult cats, Yu and Morris (1999) observed apparent sodium absorption from negative values to 82% (mean 62%) with increasing levels of dietary sodium ( g/kg [6 125 mg/mj ME, assuming 16-MJ ME/kg diets]). Subsequently, Teshima et al. (2010) reported sodium digestibilities of 78% in low-energy diets (13.7 MJ ME/kg) and 89.5% in high-energy diets (16.8 MJ ME/kg). In all studies, apparent sodium absorption rate increased with sodium intake, but sodium faecal output was not significantly affected by dietary sodium content or total sodium intake, suggesting nearly 100% absorption of ingested sodium. Those studies reported sodium faecal outputs from 12.0 mg per cat/day [with dietary sodium levels of g/kg (6 125 mg/mj ME)] using 12 adult cats (BW 3.9 kg; Yu and Morris, 1999) to 13.1 mg/cat/ day [with dietary sodium levels of g/kg ( mg/mj ME, assuming 16-MJ ME/kg diets)] using 12 kittens (11 week of age; BW 2.1 kg; Yu and Morris, 1997). Both studies used purified diets. However, Finco et al. (1989) reported faecal sodium losses of 23 mg/day and 34.5 mg/day in adult cats fed commercial dry cat food, when sodium intakes were 0.4 and 0.9 g/day respectively. Ching et al. (1989) reported an apparent sodium absorption rate of 85 90% regardless of the sodium intake that ranged from 68 to 95 mg/kg BW/day in adult cats. In various studies in healthy cats (aged 8 months to 9 years) that ingested diets differing in level of sodium, average faecal endogenous sodium output was 3.9 mg/kg BW per day and average renal endogenous loss was 6.7 mg/kg BW per day (n = 32) (Zentek, 1987; Schneider, 1988; Figge, 1989; Schuknecht, 1991; Wilms-Eilers, 1992; Dekeyzer, 1997; Journal of Animal Physiology and Animal Nutrition 101 (2017) Blackwell Verlag GmbH 405

4 Sodium in feline nutrition P. Nguyen et al. Schultz, 2003; Fig. 2). Recently, Paßlack et al. (2014) reported faecal sodium output of mg/kg BW per day, regardless of sodium intake, in healthy cats (aged months) fed diets containing mg/mj ME sodium for 3 weeks. However, in this experiment, apparent sodium absorption (and retention) increased linearly in relation to dietary sodium concentration and intake. Prola et al. (2010), in agreement with earlier studies by Kienzle (1989), found that in adult cats fed diets for 1 week with different cellulose types added at a level of 4%, faecal excretion of sodium was exponentially correlated with faecal water (R 2 = 0.81), faecal bulk (R 2 = 0.77) and (to a lesser extent) faecal dry matter excretion (R 2 = 0.55). Some factors may affect dietary sodium digestion and absorption in cats. Dietary factors include those related to faecal bulk and water content. Largely fermentable fibre sources increase the water content of faeces, and the type and inclusion level of non-fermentable fibre increase faecal bulk, leading to increased faecal sodium excretion (Kienzle, 1989; Prola et al., 2010). On the other hand, few studies have investigated factors that affect sodium absorption in cats. Teshima et al. (2010) only reported that sodium absorption was not age dependent in 18 adult cats aged 1 13 years. the main control element of this balance; they respond to intake excesses or deficiencies by increasing or decreasing, respectively, sodium excretion in the urine. Therefore, sodium urinary output is strongly correlated with sodium intake. Various studies with healthy cats (aged 8 months to 9 years) with different sodium intake levels showed a close relationship between sodium intake and sodium urinary excretion (Fig. 2). Per mg/kg BW/day sodium intake, sodium urinary excretion increased in average by 0.75 mg/kg BW per day (Zentek, 1987; Schneider, 1988; Figge, 1989; Schuknecht, 1991; Wilms-Eilers, 1992; Dekeyzer, 1997; Schultz, 2003). In these studies, neither sodium faecal output nor sodium retention (calculated as sodium intake minus sodium faecal output minus sodium urinary output) was directly related to sodium intake. Nevertheless, Paßlack et al. (2014) recently reported that sodium retention increased linearly from 126 to 469 mg/day in cats fed four diets containing mg/mj ME sodium for 3 weeks each. Differences in sodium retention could be related to relatively short duration of the trials, and changes in body sodium stores (skin, skeletal muscle), whose determinants are not fully known yet (Titze, 2014). Even more total body sodium would fluctuate independent of intake according to a circaseptan (about weekly) rhythmicity (Titze et al., 2014, 2015). Sodium urinary output As mentioned above, various regulatory mechanisms effectively maintain sodium homeostasis in the body despite variable intakes and losses. The kidneys are Sodium dietary requirements Due to a lack of specific data, the NRC s initial (1986) recommendations for minimal sodium requirements were based on the requirements of other small 300 Sodium excretion (mg/kg BW/d) Renal excretion y = x R² = Faecal excretion y = x R² = Sodium intake (mg/kg BW/d) Fig. 2 Correlation between sodium intake and faecal (triangles) and renal (squares) excretion in adult cats fed various experimental and commercial diets (Zentek, 1987; Schneider, 1988; Figge, 1989; Schuknecht, 1991; Wilms- Eilers, 1992; Dekeyzer, 1997; Schultz, 2003; Paßlack et al., 2014). 406 Journal of Animal Physiology and Animal Nutrition 101 (2017) Blackwell Verlag GmbH

5 P. Nguyen et al. Sodium in feline nutrition mammals. These requirements were set at 0.5 g sodium per kg dry food (310 mg/mj ME, assuming a dietary energy density of 16 MJ ME/kg, that is approximately mg/kg BW per day in cats in which daily energy requirement would be kj/kg BW). Later, Yu and Morris (1997, 1999) estimated the sodium requirements of growing kittens and adult cats based on plasma aldosterone levels. Such measurements may lead to an overestimation of sodium dietary requirements because increases in aldosterone conserve sodium and ensure normality at low sodium intake. Nevertheless, the NRC more recently (2006) based its minimum requirement recommendations (adult cats: 10.6 mg/kg BW per day) on the studies of Yu and Morris (1997, 1999) plus an additional margin to account for increased faecal output in cats fed commercial diets. Although no similar studies exist for gestating and lactating queens, the NRC (2006) established recommended sodium requirements based on the literature: 740 mg/mj ME for growing kittens and 40 mg/mj ME for adult cats at maintenance. The recommended allowance is 205 mg/mj ME for growing kittens and gestating queens, 40 mg/mj ME for adult cats and 160 mg/mj ME for queens at peak lactation. European Pet Food Industry Federation (FEDIAF, 2014) recommendations take into account the results of Yu and Morris (1997, 1999) and added safety margins of approximately 25% in adult cats and 30% in growing kittens. FEDIAF set its recommended minimum at 45 mg/mj ME and 95 mg/mj ME sodium for adult and growing, gestating or lactating cats respectively. The SUL suggested by the National Research Council (2006) was based on Yu and Morris (1997), which reported no adverse effects in kittens consuming a diet containing 10 g/kg sodium, and Burger (1979), who reported no abnormalities in adult cats consuming diets containing >15 g/kg sodium (935 mg/mj ME, assuming a 16-MJ ME/kg diet) as long as water was freely available. Toxicological studies of the effects of higher sodium levels in cats are lacking; in accordance with available data, the NRC set the SUL for sodium at 765 mg/mj ME for both adult and growing cats. Yu and Morris (1997) described clinical signs of sodium deficiency in sodium-depleted kittens (12 15 weeks of age; sodium intake: 1.9 mg/kg BW per day). These signs included anorexia, impaired growth, polyuria, polydipsia, haemoconcentration, reduced urinary specific gravity and elevated plasma aldosterone concentrations. Dietary sodium and feline health implications The sodium content of cat foods has been controversial due to the human health implications of high sodium intake. In humans, habitual high dietary sodium intake has been associated with the development of hypertension, hypertension-related cardiovascular diseases (Institute of Medicine, 2004), renal diseases (Ritz et al., 2009), gastric mucosal damage and gastric cancer (Tsugane et al., 2004; Kono et al., 1983; Tsugane and Sasazuki, 2007). However, the implications of dietary sodium reduction on blood pressure are controversial. Although epidemiological studies in humans reported significant relationships between high sodium intake and higher blood pressure, intervention studies that restricted dietary salt to lower blood pressure have yielded mixed results in both normotensive and hypertensive subjects (He and Macgregor, 2004; Jurgens and Graudal, 2004; Hollenberg, 2006). Nonetheless, there seems to be sufficient evidence to conclude that moderate salt intake may be a valid therapeutic approach in patients with renal disease or other sodium-retaining conditions. However, the data do not support any benefit in healthy individuals (Drake-Holland and Noble, 2011; Satin, 2011). Moreover, further studies agree that hypertension is caused by multiple factors and that individuals vary in their salt sensitivity, defined as increased blood pressure responsiveness to alterations in dietary sodium intake (Weinberger, 1996; Kusche-Vihrog and Oberleithner, 2012). Given this open debate about the role of dietary sodium in human health, what is known in feline medicine? Multiple studies of various dietary sodium levels and their effects on different aspects of cat health have been published since the early 1990s; however, some of these studies usually suffered from limitations (e.g. very short-term studies, or studies using diets that differed not only by their sodium content) that may hamper their applicability. In pet nutrition, high or low dietary sodium levels have not been clearly defined outside of the NRC guidelines (2006). Table 1 summarizes the sodium content (in mg/mj ME) of the most popular prescription commercial cat foods in Europe. It includes diets claiming reduced or increased sodium content (diets for urolithiasis therapy, for renal disease and for cardiac disease). Dietary sodium in feline urolithiasis therapy and management It is often argued that a high-salt diet promotes the development of calcium-containing kidney stones in Journal of Animal Physiology and Animal Nutrition 101 (2017) Blackwell Verlag GmbH 407

6 Sodium in feline nutrition P. Nguyen et al. Table 1 Sodium content of major feline prescription diets for renal, cardiac, and urolithiasis patients (Updated, June 2016) Diet Dry/Wet Sodium content (mg/mj) Prescription diets for cats with renal diseases Affinity Advance veterinary D diets renal feline formula * Hill s Prescription diet feline D k/d kidney care * Hill s Prescription diet feline W k/d kidney care * Purina ProPlan veterinary D diet feline NF renal function Purina ProPlan veterinary W diets feline NF renal function Royal Canin veterinary diet D feline renal RF 23 Royal Canin veterinary diet D renal select RSE 24 Royal Canin veterinary diet W feline renal Specific kidney support FKD * D Specific kidney support FKW * W Virbac Vet Complex renal * D Prescription diets for cats with urolithiasis Affinity Advance veterinary D diets feline formula urinary Hill s Prescription diet feline D c/d urinary care Hill s Prescription diet feline W c/d urinary care Hill s Prescription diet feline s/d D urinary dissolution Hill s Prescription diet feline s/d W urinary dissolution Purina ProPlan veterinary D diets feline UR St/Ox urinary Purina ProPlan veterinary W diets feline Ur St/Ox urinary Royal Canin veterinary diet D feline urinary S/O LP 34 Royal Canin veterinary diet feline W urinary S/O Royal Canin veterinary diet feline D urinary S/O high dilution UHD 34 Specific crystal prevention FCD D Specific crystal prevention FCW W Specific struvite dissolution FSD D Specific struvite dissolution FSW W Virbac Vet Complex urology D Metabolisable energy (MJ/kg) *Diets also recommended, by the manufacturers, for cardiac diseases in feline patients. humans. This conclusion is based on the high prevalence of hypercalciuria in calcium oxalate urolith formers and the direct relationship between sodium intake and urinary calcium excretion (Cappuccio et al., 1993; Saggar-Malik et al., 1996). Sodium-induced calciuria is believed to result from sodium calcium interactions in the renal tubules. It is hypothesized that high sodium intake can lead to an upregulation of specific calcium transport molecules in the distal tubule of the nephron (Lee et al., 2012). However, its exact mechanism and its relative importance in calcium oxalate urolith formation are still unclear (Logan, 2006). In feline nutrition, the effects of dietary sodium on calcium oxalate uroliths are similarly controversial. The effect of sodium intake on calciuria is inconclusive based on the existing data. Kirk et al. (2006) found a significant increase over 12 weeks in fractional urinary calcium excretion in 18 cats fed a diet containing 695 mg/mj ME sodium vs. 18 cats fed a diet with 215 mg/mj ME sodium (p < 0.01; Table 2). Devois et al. (2000) detected an increase in total urinary calcium excretion in six cats fed a diet of 560 mg/mj ME sodium over 12 days, although urinary calcium concentration was significantly lower than that of cats fed diets with <240 mg/mj ME sodium (Table 2). In contrast, Hawthorne and Markwell (2004) and Xu et al. (2009) reported no significant effect of dietary sodium levels (>655 mg/mj ME vs. <420 mg/mj ME over 3 weeks and 695 mg/mj ME vs. 335 mg/mj ME over 6 months, respectively) on urinary calcium excretion. A retrospective case control study (Lekcharoensuk et al., 2001) of 173 cats determined that cats fed diets containing high sodium levels ( mg/mj ME) were approximately half as likely (odds ratio 0.48) to develop calcium oxalate uroliths as cats fed lowsodium diets ( mg/mj ME). Although the effectiveness of modifying sodium intake on increasing or reducing calcium oxalate urolith formation in feline urolithiasis patients has not been tested, studies have confirmed that increasing the dietary intake of sodium significantly reduces the relative supersaturation (RSS) of calcium oxalate in healthy cats (Tournier et al., 2006; Xu et al., 2006). The calculation of RSS from the urine of cats fed a specific diet can be used to study the effect of that diet on the crystallization potential of their urine (Markwell et al., 1998; Robertson et al., 2002). Tournier et al. (2006) evaluated 11 extruded diets with a sodium content of approximately mg/mj ME (assuming 16 MJ ME/kg of food) on urinary parameters in healthy cats. A significant linear correlation was found between dietary sodium and calcium oxalate RSS with increasing urine volume (and thus urine dilution). Diets with high moisture content have also been shown to reduce calcium oxalate RSS in urolith-forming cats (Lulich et al., 2004). 408 Journal of Animal Physiology and Animal Nutrition 101 (2017) Blackwell Verlag GmbH

7 P. Nguyen et al. Sodium in feline nutrition Table 2 References and main results related to sodium intake levels in feline health Reference Number and characteristics of animals in each group Dietary sodium content Duration of the feeding period Study design Parameters evaluated Limitations Devois et al. (2000) Buranakarl et al. (2004) Hawthorne and Markwell (2004) Luckschander et al. (2004) 6 healthy adult cats 5 commercial diets: mg/mj ME 7 healthy adult cats 14 adult cats with experimentally induced impaired renal function 165 vs. 330 vs. 660 mg/mj ME 6 healthy adult cats 10 diets with <95 mg/mj ME vs. 13 diets with mg/mj ME 10 healthy adult cats 285 vs. 620 mg/mj ME 14 days Randomized crossover Kirk et al. (2006) 5 healthy adult acts 5 obese cats 5 older cats (>10 years) 3 cats with renal insufficiency (Plasma creatinine >132 lmol/l) 12 days Sequential feeding Urinary calcium concentration Urinary RSS with calcium oxalate 7 days Sequential feeding Systolic blood pressure Serum sodium, serum potassium Fractional excretion of sodium BUN Serum creatinine Urinary protein-to-creatinine ratio GFR Plasma renin, plasma aldosterone, aldosterone renin ratio Plasma vasopressin 21 days Observational Water intake Urine volume Urine specific gravity Urinary RSS with calcium oxalate 215 vs. 695 mg/mj ME 12 weeks Randomized, controlled, blind trial Systolic blood pressure Water intake Urine volume Urine specific gravity Mean arterial pressure Body composition (DEXA) Bone mineral density (DEXA) Water intake Urine volume Urine specific gravity Urine ph Urinary excretion of sodium Fractional excretion of calcium BUN Serum creatinine Serum phosphorus Left ventricular diameter at systole and diastole Ocular fundic examination Intraventricular septum thickness Fractional shortening Aortic outflow Plasma antidiuretic hormone, renin activity Plasma aldosterone Diets differed not only by their sodium content Experimentally induced kidney disease Reported significant high BP of the old cats at the beginning of the study Evidence grade* IV III IV IV III Journal of Animal Physiology and Animal Nutrition 101 (2017) Blackwell Verlag GmbH 409

8 Sodium in feline nutrition P. Nguyen et al. Table 2 (Continued) Reference Number and characteristics of animals in each group Dietary sodium content Duration of the feeding period Study design Parameters evaluated Limitations Xu et al. (2006) 9 healthy adult cats 240 vs. 500 vs. 740 mg/mj ME Cowgill et al. (2007) 5 healthy adult cats 120 vs. 765 mg/mj ME 4 or 6 months Randomized crossover Xu et al. (2009) 12 healthy mature ( years) cats Reynolds et al. (2013) 20 healthy mature ( years) cats 14 days Sequential feeding Water intake Urine volume Urine specific gravity Urine ph Urinary excretion of sodium Urinary excretion of calcium Urinary RSS with calcium oxalate Urinary RSS with struvite 335 vs. 695 mg/mj ME 6 months Randomized, controlled 240 vs. 740 mg/mj ME 24 months Randomized, controlled, blinded Total body water (bioimpedance) BUN Serum creatinine GFR Systolic blood pressure Body composition (DEXA) Bone mineral density (DEXA) Urine specific gravity Urinary excretion of sodium Urinary excretion of calcium Urinary excretion of oxalate Urinary excretion of citrate Urine protein Urinary protein-to-creatinine ratio BUN Serum creatinine Serum phosphorus Serum calcium Serum sodium Serum potassium Systolic and diastolic blood pressure Urine specific gravity Urine albumin Urine aldosterone Urinary protein-to-creatinine ratio Urinary sodium-to-creatinine ratio Urine ph General blood chemistry, parathyroid hormone concentrations General haemogram Plasma renin activity Plasma aldosterone GFR Renal resistive index Evidence grade* III IV III II 410 Journal of Animal Physiology and Animal Nutrition 101 (2017) Blackwell Verlag GmbH

9 P. Nguyen et al. Sodium in feline nutrition Table 2 (Continued) Reference Number and characteristics of animals in each group Dietary sodium content Duration of the feeding period Study design Parameters evaluated Limitations Paßlack et al. (2014) Chetboul et al. (2014) 8 healthy adult cats (12 25 months) 20 healthy mature ( years) cats 220 vs. 380 vs. 670 vs. 830 mg/mj ME 3 weeks Sequential feeding Water intake Urine volume Sodium faecal output Sodium renal excretion Urine RSS 240 vs. 740 mg/mj ME 24 months Randomized, controlled, blinded Systolic and diastolic blood pressure Standard echocardiography examination (9 criteria) Conventional Doppler examination (3 criteria) Two-dimensional colour tissue Doppler imaging: radial and longitudinal velocity of the left ventricular free wall and interventricular septum in diastole and systole (11 criteria) BUN, blood urea nitrogen; DEXA, dual-energy X-ray absorptiometry; GFR, glomerular filtration rate; ME, metabolizable energy; RSS, relative supersaturation. *According to Roudebush et al. (2004). Parameters that significantly different among sodium intake groups in the study. Spot samples. Evidence grade* III II Journal of Animal Physiology and Animal Nutrition 101 (2017) Blackwell Verlag GmbH 411

10 Sodium in feline nutrition P. Nguyen et al. High dietary sodium content resulted in higher production (due to increased water intake; Burger, 1979; Burger et al., 1980) of urine with lower specific gravity (Hawthorne and Markwell, 2004; Kirk et al., 2006; Paßlack et al., 2014). Moreover, higher dietary sodium content was associated with both higher calcium concentration and lower oxalate urinary concentration, such that calcium oxalate RSS was not affected by sodium intake (Paßlack et al., 2014). It is plausible to assume that the effects of sodium on water intake and its diluting effect on urine calcium concentration are relatively greater than the possible effect of sodium on promoting urine calcium excretion. In contrast to oxalate stones, pure struvite uroliths can be dissolved with a diet that promotes higher urine volume and more acidic urine (Osborne et al., 1990; Houston et al., 2004). Although the specific effects of sodium levels on the dilution and prevention of struvite uroliths have not been reported in cats, high levels of sodium have been used in foods shown to be effective for struvite dissolution in feline patients. Osborne et al. (1990) achieved dissolution of sterile struvite uroliths in 20 feline patients fed a calculolytic diet with high moisture, low magnesium content, urine-acidifying capabilities and augmented sodium content (360 mg/mj ME). Houston et al. (2011) also obtained positive effects on struvite urolith dissolution in 10 feline patients with a diet with RSS <1 and sodium contents of 310 mg/mj ME (canned formula, n = 5) or 550 mg/mj ME (dry formula, n = 5). On the other hand, Lekcharoensuk et al. (2001) reported that out of 290 cats, cats fed diets containing mg/ MJ ME sodium were 4.1 times as likely to develop struvite uroliths as cats fed diets containing mg/mj ME sodium. However, this study also detected a significant correlation between high sodium content and high phosphorus content in these diets, which may have influenced this effect. Effects of dietary sodium on blood pressure The relationship between dietary sodium and blood pressure in human has been discussed for decades. Various types of investigations, including animal (laboratory rodent) experiments and human genetics, epidemiology, population-based intervention and treatment trials, have addressed the implications of sodium intake on blood pressure as well as the underlying mechanisms (Ha, 2014). Although a certain amount of agreement exists regarding the contribution of high salt intake to hypertension (Swift et al., 2005), the mechanisms underlying this contribution are not fully understood. Hypertensive mechanisms that possibly respond to sodium intake include individual-specific impaired sodium regulation, chronic increases in the amount of extracellular fluid and increases in sympathetic activity (de Wardener, 2001) or signalling (aldosterone, angiotensin II pathways) that directly affects central (cardiovascular control centres) and peripheral (smooth muscle) molecular mechanisms that cause and maintain blood pressure increases (Blaustein et al., 2012). Hypertension is increasingly observed in feline patients, presumably due to increased awareness of the problem. Although idiopathic hypertension in cats accounts for approximately 20% of cases of elevated blood pressure in cats (Maggio et al., 2000; Elliott et al., 2001), secondary hypertension is reportedly the most common category (Brown et al., 2007). The clinical problems most frequently associated with hypertension in cats are chronic kidney disease (CKD) (20 60%) and hyperthyroidism (10 20%) (Syme et al., 2002). The main consequence of hypertension is injury to tissues that chronically sustain elevated blood pressure (target-organ damage). In accordance with clinical data, the consensus statements of the American College of Veterinary Internal Medicine (ACVIM) (Brown et al., 2007) defined the following feline populations as at risk for hypertension: middleaged to older cats (9 12+ years); cats with diseases associated with feline hypertension; and cats with neural, ocular and/or cardiac abnormalities (which may be caused by target-organ damage). According to the ACVIM consensus statements (Brown et al., 2007), cats with systolic blood pressure >180 mm Hg are at severe risk for future target-organ damage. Major therapeutic actions for hypertensive feline patients include antihypertensive drug therapy and treatment of the primary cause, if known (Brown et al., 2007). Traditionally, low-sodium diets have been recommended for cats with hypertension based primarily on data from laboratory animals and human studies. Five studies reported the effects of various sodium intake levels on blood pressure in cats (Table 2). In a randomized crossover study with 10 healthy young adult cats fed 620 mg/mj ME sodium over 14 days, no differences in systolic blood pressure (measured via Doppler) were found vs. a diet of 285 mg/mj ME sodium in the same cats (Luckschander et al., 2004). Moreover, Kirk et al. (2006) observed no differences over 3 months in five healthy adult cats fed 215 vs. 695 mg/mj ME sodium. Data on at-risk feline populations are also available from three randomized, controlled studies of aged, healthy cats (Kirk et al., 2006; Xu et al., 2009; Reynolds et al., 2013) and a trial with 412 Journal of Animal Physiology and Animal Nutrition 101 (2017) Blackwell Verlag GmbH

11 P. Nguyen et al. Sodium in feline nutrition an experimental model of impaired renal function in cats (Buranakarl et al., 2004). Xu et al. (2009) reported no differences in systolic blood pressure (measured by Doppler) between 12 healthy, aged (mean age 7 years) cats fed 695 mg/mj ME sodium over 6 months and the control group of 12 aged cats fed 335 mg/mj ME sodium. Ten aged cats (mean age 10 years) fed 740 mg/mj ME sodium did not differ in terms of systolic and diastolic arterial blood pressure (measured by Doppler) after 3, 6, 12 and 24 months from the control group of 10 aged cats fed 240 mg/mj ME sodium (Reynolds et al., 2013). Buranakarl et al. (2004) reported that 14 cats with experimentally impaired renal function displayed higher blood pressure (measured by radiotelemetry) than seven cats with normal kidney function, but no changes in blood pressure occurred in any group of cats sequentially fed three diets containing 165, 330 or 660 mg/mj ME sodium for 7 days. Kirk et al. (2006) reported that blood pressure was not affected by higher levels of sodium intake (695 mg/mj ME) in a small group of cats with naturally occurring, mild increases in blood urea nitrogen (BUN; >12.5 mmol/l) and creatinine (>132 lmol/l) over 3 months. Chronic increases in the amount of extracellular fluid have been suggested to underlie the effects of sodium levels on blood pressure (de Wardener, 2001). Several studies in cats inferred that total body water reflects water retention and the volume of extracellular fluid. Cowgill et al. (2007) observed a slight rise in the absolute amount of intracellular fluid as well as increases in the relative amounts of intra- and extracellular fluids; bioimpedance measurements suggested that total body water increased in five healthy cats fed 765 mg/mj ME sodium in a crossover study over 4 months relative to the periods in which the same cats were fed 120 mg/mj ME sodium. However, Xu et al. (2009) reported no differences in total body water in 13 cats fed 695 mg/mj ME sodium vs. 13 cats fed 335 mg/mj ME sodium over 6 months, as measured via dual-energy X-ray absorptiometry. No investigations have addressed dietary sodium levels in hypertensive (primary or secondary) feline patients. The consensus statements of the ACVIM (Brown et al., 2007) concluded that there was no clear rationale for sodium restriction, although avoiding high dietary sodium chloride intake in hypertensive patients was recommended. Effects of dietary sodium on cardiovascular disease For humans with high salt intake, clinical studies previously detected higher relative risks for cardiovascular diseases such as stroke (Perry and Beevers, 1992), left ventricular hypertrophy (Kupari et al., 1994) and aortic stiffness (Avolio et al., 1986). The major possible mechanism through which dietary sodium causes cardiovascular disease is the development of high blood pressure, which may cause arterial damage and increase the risk of atherosclerosis, aneurysm, stroke and arrhythmias. Previous studies in humans also suggested that dietary salt exerts other damaging effects on the cardiovascular system that are independent of increased blood pressure (Du et al., 1992; Langenfeld and Schmieder, 1995). These effects may be due to increased mass of the left ventricle of the heart, increased thickness and stiffness of conduit arteries, the narrowing of resistance arteries and/or increased sensitivity of platelets to aggregation (Zoccali and Mallamaci, 2000). Cardiac diseases are the most common in cats, affecting up to 20% of some feline populations (Paige et al., 2009). Hypertrophic cardiomyopathy is the most common cardiac pathology in cats (Cote et al., 2004) and may lead to cardiac heart failure, feline aortic thromboembolism, syncope or sudden death. Cardiac abnormalities are frequent, occurring in 80% of hypertensive cats. Thicker ventricular wall and intraventricular septum and reduced diastolic left ventricular internal diameter were reported in these cats (Chetboul et al., 2003). In those cases, higher cardiac output is rarely the primary cause of hypertension (Maggio et al., 2000). Historically, reductions in dietary sodium have been recommended in cardiac disease as a therapeutic action for reducing fluid accumulation in animals with congestive heart failure and for ameliorating hypertension, in accordance with data obtained in laboratory animals and in humans. Current medical therapy for human patients with congestive heart failure may render severe sodium restriction less critical. Moreover, the overall effects of salt intake and its effects on blood pressure are controversial, as mentioned above. However, the International Small Animal Cardiac Health Council (1994) recommended sodium reduction interventions according to the disease stage of the patient (Table 3). In addition to the possible direct effect of high sodium intake on high blood pressure in cats (discussed above), two studies reported results related to heart functional and anatomical parameters in cats fed different amounts of dietary sodium. Kirk et al. (2006) performed a randomized, crossover study of 10 healthy adult (2 6 years) cats, 10 obese (>30% body fat) cats, 10 aged (>10 years) cats and six cats with serum creatinine levels >132 lmol/l. Diets with 215 Journal of Animal Physiology and Animal Nutrition 101 (2017) Blackwell Verlag GmbH 413

12 Sodium in feline nutrition P. Nguyen et al. Table 3 Sodium intake levels recommended by the International Small Animal Cardiac Health Council (ISACHC, 1994) for feline heart failure patients Congestive heart failure (ISACHC stages) Stage characteristics 1 Asymptomatic/ subclinical 2 Clinical signs only during exercise 3 Obvious clinical signs even at rest or 695 mg/mj ME sodium, fed over 3 months, led to no between-group differences in left ventricular enddiastolic diameter, left ventricular end-systolic diameter or thickness of the intraventricular septum, as measured by conventional echocardiography. However, the fractional shortening velocity ratio was slightly higher at the end of the high-sodium period. Nevertheless, the difference observed was clinically irrelevant and all parameters remained within the normal ranges for healthy cats. Later, Chetboul et al. (2014) carried out a trial with 20 healthy neutered cats (aged years) that were randomly allocated into two groups after they had been paired according to baseline cardiac tissue Doppler imaging and GFR. They found no differences in measured left ventricular end-diastolic diameter, isovolumic relaxation time or myocardial velocity gradient between the group fed 740 mg/mj ME sodium and the group fed 240 mg/mj ME sodium over 24 months. Those measurements are sensitive indicators of left ventricle myocardium abnormalities and early diastolic dysfunction (Chetboul et al., 2006). To date, no studies have reported the effect of dietary sodium levels on cardiac feline patients, dietary sodium as a risk factor for cardiac disease (as in humans) or the effect of sodium on the progression of cardiac disease. Effects of dietary sodium on kidney disease Recommendations for sodium intake No dietary changes are recommended, although diets with >240 mg sodium/mj ME should be avoided Intake of <190 mg sodium/mj ME recommended Intake of <120 mg sodium/mj ME recommended, unless anorexia requires higher levels Sodium restriction has been and still is recommended for human and animal patients with CKD because the loss of renal functional reserve, due to reduced ultrafiltration capacity or to enhanced tubular sodium reabsorption, induces a salt-sensitive type of hypertension (Campese, 2014). Although a meta-analysis of the evidence for the relationship between salt intake and CKD progression in humans concluded that dietary salt intake is linked with albuminuria and tissue injury, the authors acknowledged that empirical evidence is lacking (Jones-Burton et al., 2006). It has been suggested that higher sodium load is related to higher blood pressure (see above). In a hypertensive state, glomerular capillary pressure would also be elevated, resulting in glomerular sclerosis and aggravating proteinuria (Aviv, 2001; Verhave et al., 2004). Higher blood pressure and proteinuria would then lead to vascular and renal injury, potentially causing disease progression (Weir et al., 1995; Kimura et al., 2010). Moreover, other studies have suggested that high sodium intake may directly affect the kidney and vascular systems, independently of blood pressure, by increasing oxidative stress (Kitiyakara et al., 2003; Ritz et al., 2009) and leading to vascular and glomerular fibrosis, with potential declines in kidney function (Sanders, 2009). Regarding the effect of sodium intake on renal function in healthy cats and in CKD feline patients, Buranakarl et al. (2004) observed a higher GFR, a marker of renal function, in seven healthy cats fed diets containing 330 mg/mj ME sodium and 660 mg/mj ME sodium for 7 days compared with the periods in which the same cats were fed diets with 165 mg/mj ME sodium. However, in seven cats with surgically induced renal function impairment, GFR did not differ according to dietary sodium level. Moreover, this study detected no differences in renal plasma flow or urinary protein-to-creatinine ratio in healthy or renal function-impaired cats fed different sodium levels. Similarly, a randomized, controlled trial (Xu et al., 2009) reported no detectable effects on renal function in 24 middle-aged and older cats fed 335 mg/mj ME sodium or 695 mg/mj ME sodium for 6 months. There was no effect on BUN or phosphate levels measured at 3 and 6 months, but significantly lower serum creatinine levels occurred at 3 and 6 months in cats fed the high-sodium diet. However, in a subset of nine cats with baseline serum creatinine levels >140 lmol/l (four and five cats in the low- and highsalt groups, respectively), no effects were reported for serum creatinine, BUN or phosphorus levels. The most recent and long-term study assessing the effects of dietary sodium on renal health was the randomized, controlled, blind trial by Reynolds et al. (2013). In this study, 20 domestic short-haired, neutered cats (aged years) were randomly 414 Journal of Animal Physiology and Animal Nutrition 101 (2017) Blackwell Verlag GmbH

13 P. Nguyen et al. Sodium in feline nutrition allocated to two diet groups (a control diet containing 240 mg/mj ME sodium and a high-sodium diet containing 740 mg/mj ME sodium) after they had been paired according to baseline cardiac tissue Doppler imaging and GFR. In this study, there were no between-group differences in the selected renal parameters, including GFR (Table 2). Plasma aldosterone levels were lower in the high-sodium group at 3, 6, 12 and 24 months of administration. This study also measured the renal resistive index at 6, 12 and 24 months of administration. Renal resistive index provides information about renal vascular resistance (Weir, 2005). An increase has been associated with early hypertensive renal damage and correlated with increased systemic blood pressure in humans (Hanamura et al., 2012) and in cats (Novellas et al., 2010). In the study by Reynolds et al. (2013), neither left nor right renal artery resistive index changed in the 20 cats fed high or low levels of sodium. To date, only Kirk et al. (2006) have claimed that adverse renal effects may occur in cats as a result of high dietary sodium intake. They observed significantly higher slopes of initial vs. final serum creatinine, BUN and serum phosphate concentrations with high-sodium diets in both healthy cats and in cats with elevated creatinine levels and BUN. However, the significance of this observation is unclear and other indicators of renal function or damage, such as GFR and urinary protein-to-creatinine ratio, were not evaluated in this study. In contrast, Xu et al. (2009) uncovered no differences in urinary proteinto-creatinine ratio at 6 months between healthy adult cats and cats with creatinine levels >132 lmol/l. Similarly, Reynolds et al. (2013) found no differences in urinary protein-to-creatinine ratio or GFR between diet groups at 3, 6, 12 or 24 months in aged healthy cats. To date, no studies have evaluated the effects of different levels of dietary sodium on risk or disease progression in feline patients with naturally occurring CKD. Consistent with recommendations from the International Renal Interest Society (IRIS, 2009), there is currently no evidence to suggest that lowering dietary sodium intake will reduce blood pressure in cats with CKD. However, laboratory models of renal failure and human CKD patients displayed positive effects (in addition to effects on blood pressure) on CKD progression after moderate sodium intake. Data from feline patients are lacking. Alterations have also been described in the RAAS in cats fed different levels of dietary sodium (Buranakarl et al., 2004). This system exerts its vasoconstrictor effect predominantly on the post-glomerular arterioles, thereby increasing the glomerular hydrostatic pressure and the ultrafiltration of plasma proteins, which may contribute to the onset and progression of chronic renal damage. In human medicine, interventions that inhibit RAAS activity are considered to be renoprotective and may slow or even halt the progression of chronic nephropathies (Remuzzi et al., 2005). In feline medicine, the role of the RAAS in the pathogenesis of renal hypertension and the progression of renal disease is currently under investigation. Aldosterone increases have been detected in cats with naturally occurring CKD (Jensen et al., 1997; Pedersen et al., 2003). This increase may be due to increases in plasma renin activity, hyperkalaemia, altered sensitivity to stimuli of aldosterone release (e.g. concentrations of plasma renin or potassium), reduced aldosterone degradation or a combination of these factors (Hostetter and Ibrahim, 2003). In the randomized, crossover study by Kirk et al. (2006), neither plasma aldosterone levels nor renin levels differed between diet groups (215 mg/mj ME sodium vs. 695 mg/mj ME sodium over 3 months) in healthy adult (aged 2 6 years) cats, obese (>30% body fat) cats, aged (>10 years) cats or cats with mildly elevated serum creatinine levels (>132 lmol/ l). However, in the randomized, controlled study by Reynolds et al. (2013), plasma aldosterone levels in 10 aged cats fed 240 mg/mj ME sodium remained significantly higher (by fold) at 3, 6, 12 and 24 months than in 10 healthy aged cats fed 740 mg/ MJ ME sodium. Inappropriate kaliuresis was not detected in any cat during this study. Nevertheless, Buranakarl et al. (2004) investigated cats with surgically induced kidney disease and reported that sodium restriction (145 mg/mj ME) activated the RAAS (higher serum aldosterone concentrations and higher plasma renin activity), significantly lowered plasma potassium concentrations and significantly raised potassium urinary fractional excretion. In this crossover study, higher dietary levels of sodium (330 and 660 mg/mj ME) looked renoprotective because kaliuresis and RAAS stimulation were suppressed, while lower sodium intake (165 mg/mj ME) was also associated with inappropriate hypokalemic kaliuresis and activation of RAAS in induced CKD cats. It has similarly been shown that dietary salt loading can suppress activation of RAAS in rodent experimental models (Lee et al., 1991), whereas in the contrary RAAS blockade is observed during moderate sodium restriction in CKD humans (Humalda and Navis, 2014). The reasons for such interspecies differences are not known. 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