News from research - September 2015 by CoreCPH

#1 5SE PT 20 15

Adverse Food Reactions How long should an elimination trial last?

Median percentage of clinical remission in the 5 dog studies (n=209)

Available articles:

Looringh van Beeck F, Watson A, Bos M, Biourge V, Wilemse T. The effect of long-term feeding of skin barrier-fortified diets on the owner-assessed incidence of atopic dermatitis symptoms in Labrador retrievers. Journal of Nutritional Science (2015), vol. 4, e5

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Olivry T, Ralf Mueller R, Pascal Prélaud P. Critically appraised topic on adverse food reactions of companion animals (1): duration of elimination diets. BMC Veterinary Research 2015, 11:225 http://www.biomedcentral.com/1746-6148/11/225

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Elimination trial duration (weeks)

Median percentage of clinical remission in the 3 cat studies (n=40) % of clinical remission

Long term effects of the “skin barrier cocktail” on the incidence of clinical signs of atopic dermatitis (see News from Research n°10)

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Increased dietary fibre: a tool to limit hairball formation (see News from Research n°12) Weber M, Sams L, Feugier A, Michel S, Biourge V. Influence of dietary fibre levels on faecal hair excretion after 14 days in short and long-haired domestic cats. Vet Med Sci, 2015;1:30-37

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The authors conclude that to diagnose cAFR in at least 80% of dogs and cats, an elimination trial should last a minimum of 5 weeks in dogs, and 6 weeks in cats. The sensitivity of the diagnosis will increase to more than 90% of cases in both species when the duration of the elimination trial is increased to 8 weeks. The final confirmation of cAFR will be obtained after performing a provocation test with suspected food or ingredients.

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Intro Critically appraised topics: benefit from the help of talented dermatology specialists to improve your daily practice As with any field of veterinary medicine, some of what is taught in dermatology is handed down from one practitioner to the other without critical appraisal of its scientific value. Bad tips and habits are thus picked up and are never corrected. To help answer practical questions about the management of adverse food reactions, ROYAL CANIN® has initiated and supported a group of recognised veterinary dermatologists (Drs. Thierry Olivry, Ralf Mueller and Pascal Prélaud) to publish a series of “Critically appraised topics”, with the objective of reviewing existing knowledge and dogmas on this disorder. Their conclusions will result in practical tips available to both practitioners and researchers, published in the BioMed Central open access peer-reviewed journal BMC Veterinary Research. The first one (see last page) has already been downloaded more than 1100 times in two weeks. Marie-Anne Hours & Hélène Charles (R&D-Scientific Support)

Urinary Struvite stone dissolution in the urine of dogs fed ROYAL CANIN® S/O-Kcal Control This study assessed the in vitro dissolution of uroliths in sterile canine urine with struvite RSS below 1. Relative Super Saturation (RSS) is considered as the gold standard methodology to measure the risk of crystal formation or dissolution in humans, and has been validated in dog and cat urine. This method is based on the saturation level of poorly soluble salts such as calcium oxalate or struvite. In cats, a struvite RSS below 1 is predictive of both in vivo and in vitro urolith dissolution. The aim of this study was to assess whether sterile canine urine with a struvite RSS below 1 leads to in vitro struvite dissolution.

Six healthy adult Miniature Schnauzers were fed ROYAL CANIN® S/O-Kcal Control Canine dry diet for 10 days: 7 days of adaptation, followed by 3 days of collection. After pooling the urine samples collected from each dog over the 3 days, the urinary pH and the concentrations of 10 solutes (Ca2+, Mg2+, Na+, K+, NH4+, phosphate, citrate, sulfate, oxalate and uric acid) were measured to calculate RSS using the SupersatTM software. The pool of urine was then split between 25 bottles containing 30 ml each and was kept at -20°C until the dissolution test. A canine urolith analysed as 100% struvite was immersed at day 0 in a bottle of urine which was maintained at 38°C and stirred. 24 hours later, the urine was filtered to

collect the stone, which was then dried and weighed. Every day until all the urine had been used (25 days), the stone was placed in a new bottle and the procedure was repeated to monitor the dissolution of the stone. For each dog and for the pool of urine, the struvite RSS was below 1. After 25 days, 60% of the struvite urolith had dissolved. Sterile canine urine with struvite RSS below 1, obtained from dogs fed ROYAL CANIN® S/O-kcal control, effectively dissolves struvite stone. Sagols E, Moniot D, Defiez A, Faur E, Nuns C, Billy H, Queau Y. A struvite RSS below 1 is predictive of in vitro struvite dissolution in dog urine. Proceedings of the 40th WSAVA congress, Bangkok (Thailand), May 15-18, 2015

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Kinetics of canine struvite stone dissolution in urine with struvite RSS < 1

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Elimination trial duration (weeks)

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Hot off the press!

In these articles, the diagnosis of cAFR was made after the exclusion of other relevant causes of pruritus and a complete or marked improvement of clinical signs after feeding an elimination diet (including novel or hydrolysed ingredients). Patients were then confirmed as having cAFR after the recurrence of signs when the previous food items were reintroduced.

With the information gathered from these studies involving 209 dogs and 40 cats with cAFR, the group of specialists estimated that: - From 5 weeks onwards, clinical signs had disappeared in more than 85% of dogs, increasing to over 95% if the trial was extended to 8 weeks. - It took approximatively 4, 6 and 8 weeks of an elimination diet for 50, 80 and 90% of cats to achieve a clinical remission, respectively.

Performing a dietary restrictionprovocation test (“elimination trial”) is considered to be the standard procedure to diagnose cutaneous Adverse Food Reactions (cAFR) in dogs and cats. However, there is no consensus available on the optimal duration of such trials, and recommendations have varied from 3 to 12 weeks.

The authors (Drs.Thierry Olivry, Ralf Mueller and Pascal Prélaud) searched out and analysed the scientific literature available. They selected eight papers providing specific data on the time needed for clinical signs of cutaneous AFR to improve in patients fed an elimination diet (5 in dogs, 3 in cats).

% of clinical remission

The first “critically appraised topic” on adverse food reactions in companion animals aimed at reviewing existing knowledge on the duration of elimination trials. A group of recognised dermatology specialists determined that they should last at least 8 weeks to allow diagnosis in more than 90% patients.

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Digestive sensitivity of dogs according to size: knowledge and nutritional strategies from 16 years of research Colonic and total transit time according to dog size (adapted from Hernot et al, 2006) Time (h)

Since 1998 different studies performed in collaboration with the National Veterinary School of Nantes (now Oniris) allowed us to better understand why large breed dogs present an increased frequency of soft faeces and how we can improve faeces quality of dogs by adapting diet formulation. A summary of the physiological knowledge we have acquired and subsequent nutritional “tips” was presented at the ACVIM1 congress last June.

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CTT TTT

Another study confirmed that this longer CTT results in higher fermentative activity in large breed dogs, with significantly higher concentrations of lactic acid and total shortchain fatty acids (SCFA). The large quantity of organic acids produced could thus exceed the absorption capacity of the colonic mucosa, leading to their accumulation in the colonic lumen. Intra-luminal osmotic pressure would therefore increase, leading to high water secretion in the colon and subsequent poorer faecal consistency. These CTT and fermentative activity differences are linked to anatomical differences: the volume of the colon was shown to be 47 times higher in Great Danes than in Minitature Spitz, caecum volume representing 48% of large intestine volume in Great Danes whereas it represented only 6% in Beagles. American College of Veterinary Internal Medicine 2 NFR#5: News from Research n°5 3 NFR#7: News from Research n°7 1

TTT : Total Transit Time

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MP : Miniature Poodle MS : Medium Schnauzer GS : Giant Schnauzer GD : Great Dane

Nutritional recommendations according to size Protein quantity and protein digestibility both impact the consistency of faeces. The more digestible the protein, the less undigested nutrient will reach the colon to be fermented, thus improving the faecal score. The indigestible share of protein increases in proportion to the total protein content, therefore keeping the amount of protein moderate could be a way to improve faecal consistency.

Weber M, et al. Am J Vet Res. 2002;63:1323. Weber M, et al. Am J Vet Res. 2002;63:677. Weber M, et al. J Anim Physiol Animal Nutr. 2003;87:1. Weber M, et al. Am J Vet Res. 2003;64:1105. Hernot D, et al. European College of Veterinary Internal Medicine. Uppsala, Sueden; 2003. Weber M, et al. J Anim Physiol Anim Nutr. 2004;88:356. Hernot D, et al. J. Anim Physiol Anim Nutr. 2005;89:189. Hernot D, et al. Am J Vet Res. 2006;67:342. Hernot D, et al. J Anim Physiol Anim Nutr. 2009;93:703. Nery J, et al. J Anim Sci. 2010;88:159. Goudez R, et al. Br J Nutr. 2011;106:S211-215. Nery J, et al. J Anim Sci. 2012:90:2570. Goudez R, et al. Proc. of the 12th AAVN Clinical Nutrition and Research Symposium 2012. Goudez R, et al. Proc. of the 16th ESVCN congress, September 2012, Bydgoszcz, Poland. p91

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The sources and forms of starch and their processing strongly influence stool quality. In large breed dogs, an increase in resistant starch (low digestibility) leads to a significant decrease in stool quality; maize and rice appear to be the best sources regarding digestive tolerance, and purified starches further improve stool consistency (see NFR#52). Starch processing has an impact on all breed sizes: a decrease in the “cooking” of starch leads to a significant increase in the number of unacceptably soft stools in both small and large dogs (see NFR#73).

ROYAL CANIN® supported the thesis of Rebecca Geddes, which aimed at better characterising feline CKD-MBD (Chronic Kidney Disease-Mineral and Bone Disorder), the role of FGF-23, and responses to dietary phosphate restriction in healthy and azotemic cats. The first studies validated FGF-23 (fibroblast growth factor 23) measurements in cats and showed that FGF-23 increases as CKD increases in severity, and is higher in hyperphosphatemic than in normophosphatemic cats, even within the same IRIS stage. The plasma FGF-23 concentration at diagnosis of CKD is an independent predictor of the progression of azotemia within 12 months and of survival time: the risk of death is doubled for cats

with 3000 < FGF-23 < 10000 pg/ml, and quadrupled for cats with FGF-23 >10000 pg/ ml at the time of diagnosis, as compared to cats with normal FGF-23 levels (≤ 700 pg/ml). The effect of phosphate restricted diets (Renal range) were then assessed in a retrospective study (see details in NFR#114) and a prospective study involving 43 euthyroid cats. Both studies showed that phosphate restriction induces a reduction in FGF-23 concentration in all cats, even normophosphatemic cats for which plasma phosphate and PTH did not significantly change. The possible link between a low plasma FGF-23 at baseline and a later development of ionized hypercalcemia requires further investigation.

to healthy older cats is associated with a decrease in the urinary excretion of phosphate and a prevention of what may be an age-related increase in plasma PTH concentration or the development of secondary hyperparathyroidism, when compared to feeding an adult maintenance diet. As only few cats developed CKD during the study, it was not possible to conclude if a senior diet can reduce the proportion of cats that develop CKD. A genetic study in the same cats showed that cats that developed hypercalcemia displayed the same mutations of the calcium receptor fCaSR. FGF-23 can be a useful tool to assess CKD-MBD and predict the evolution of CKD in cats. Phosphate restriction is efficient in reducing FGF-23 and PTH plasma concentrations; a moderate restriction may prevent age-related PTH increase in apparently healthy old cats. As some cats are genetically predisposed to more severe CKD-MBD, it is essential that cats suffering from CKD receive tailored management.

Another 18 month-prospective study involved 54 healthy cats above the age of 9 years old. It showed that feeding a senior diet (protein and phosphate moderately restricted)

Effect of resistant starch on stool quality (faecal scores) according to dog size (adapted from Goudez et al, 2011) German Shepherds 100%

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resistant starch (% dry matter) Optimal scores

Survival of cats based on plasma FGF-23 concentration at diagnosis of CKD

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(adapted from Geddes R. PhD thesis, 2014). FGF-23 ≤ 700 pg /ml

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Percent survival

The studies confirmed the impact of breed size on faecal consistency, with a strong positive correlation between moisture content of the faeces and body weight of the dog (r=0.89, p<0.0001). However, contrary to what was expected, the upper gastrointestinal transit time (stomach + small intestine) and intestinal absorption capacity are not different between dog sizes, and the apparent digestibility of nutrients and gross energy is higher in large than in small breed dogs. The explanation for more frequent soft stools in large breed dogs lies in the colon: colonic transit time (CTT) and total transit time (TTT) are positively correlated with body size, and the part of CTT in TTT varies between small and large breed dogs (mean CTT 9.1±1.1 and 39.4±1.6 hours, accounting for 39% and 70% of mean TTT respectively).

Publications:

Characterisation of CKD-MBD and the effect of dietary phosphate restriction on its prevention or reversal.

CTT TTT

CTT : Colonic Transit time

Differences in digestive physiology according to size

M. Weber (1998-2002): Influence of size on dog digestive function D. Hernot (2002-2006): Influence of size on digestive tolerance and colonic function in dogs J. Nery (2006-2010): Influence of quantity and quality of proteins on digestive tolerance in dogs - Effect of body size R. Goudez (2010-2014): Influence of starch and extrusion process on digestive tolerance in dogs - Effect of body size

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In summary, large breed dogs present digestive characteristics that must be taken into account in their daily diet. Prolonged colonic transit and a large colon size compared with smaller dogs are elements that promote colonic fermentation and soft stools. When choosing a particular diet in order to improve large dogs’ stool quality, the general goal is to avoid any ingredient that could increase the level of fermentable undigested residues and, in fine, exacerbate colonic fermentation.

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Lastly, the source and content of fibre both have an impact on faecal consistency, with differences according to size: in large breed dogs, stool quality is improved with the incorporation of non-fermentable fibre (i.e. cellulose) while fermentable fibre (especially fructo-oligosaccharides) quickly induces soft stools. On the contrary, small dogs are tolerant toward the inclusion of fermentable fibre but too much cellulose can induce constipation. An optimal ratio of fermentable and non-fermentable fibre is essential, and will be different between small and large breed dogs.

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FGF-23 > 10000 pg /ml

PhDs: R. Geddes (2010-2014): Calcium-Phosphate homesostasis in Feline Chronic Kidney Disease Publications: Geddes R.F., et al. J Vet Intern Med. 2012 (abstract). Geddes R.F., et al. J Vet Emerg Critical Care. 2013;23(2):122-133. Geddes R.F., et al. J Vet Intern Med. 2013;27(2):234-241. Geddes R.F., et al. J Vet Intern Med. 2013;27(6):1354-1361. Geddes R.F., et al. J Vet Intern Med. 2013;27 (abstract). Geddes R.F., et al. Proceedings of the British Small Animal Veterinary Association Congress. 2014 (abstract).

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resistant starch (% dry matter) Unacceptable scores

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NFR#11: News from Research n°11