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Received: 20 July 2016    Accepted: 13 January 2017

DOI: 10.1111/jpn.12692

ORIGINAL ARTICLE

A longitudinal study on the acceptance and effects of a


therapeutic renal food in pet dogs with IRIS-­Stage 1 chronic
kidney disease

J. A. Hall1  | D. A. Fritsch2 | M. Yerramilli3 | E. Obare3 | M. Yerramilli3 | D. E. Jewell2

Summary
1
Department of Biomedical Sciences, College
of Veterinary Medicine, Oregon State
University, Corvallis, OR, USA Currently, nutritional management is recommended when serum creatinine (Cr) ex-
2
Pet Nutrition Center, Hill’s Pet Nutrition, Inc, ceeds 1.4 mg/dl in dogs with IRIS-­Stage 2 chronic kidney disease (CKD) to slow pro-
Topeka, KS, USA
gressive loss of kidney function, reduce clinical and biochemical consequences of
3
IDEXX Laboratories, Inc, Westbrook, ME,
CKD, and maintain adequate nutrition. It is unknown if dietary interventions benefit
USA
non-­azotemic dogs at earlier stages. A prospective 12-­month feeding trial was per-
Correspondence
formed in client-­owned dogs with IRIS-­Stage 1 CKD (n = 36; 20 had persistently dilute
J. A. Hall, Department of Biomedical Sciences,
College of Veterinary Medicine, Oregon State urine with urine specific gravity (USG) <1.020 without identifiable non-­renal cause; six
University, Corvallis, OR, USA.
had persistent proteinuria of renal origin with urine protein creatinine (UPC) ratio
Email: Jean.Hall@oregonstate.edu
>0.5; 10 had both). Ease of transition to therapeutic renal food and effects on renal
Funding information
The work presented in this study was funded biomarkers and quality of life attributes were assessed. Dogs were transitioned over
by Pet Nutrition Center, Hill’s Pet Nutrition,
1 week from grocery-­branded foods to renal food. At 0, 3, 6, 9, and 12-­months a ques-
Inc, Topeka, KS (http://www.hillspet.com/
our-company.html). Hill’s Pet Nutrition, Inc tionnaire to assess owner’s perception of their pet’s acceptance of renal food and
and IDEXX Laboratories, Inc provided support
quality of life was completed. Renal biomarkers, including serum Cr, blood urea nitro-
in the form of salaries for authors [DAF,DEJ]
and [Maha Y, EO, Murthy Y], but did not have gen (BUN), and symmetric dimethylarginine (SDMA), and USG and UPC ratio were
any additional role in the study design, data
measured. Of 36 dogs initially enrolled, 35 (97%) dogs were transitioned to therapeu-
collection and analysis, decision to publish, or
preparation of the manuscript. tic renal food. Dogs moderately or extremely liked the food 88% of the time, ate most
or all of the food 84% of the time, and were moderately or extremely enthusiastic
while eating 76% of the time. All renal biomarkers (Cr, BUN, and SDMA) were
­decreased (p ≤ .05) from baseline at 3-­months, and remained decreased from baseline
at 12-­months in dogs completing the study (n = 20). Proteinuria was reduced in 12 of
16 dogs (p = .045) with proteinuria. Owners reported improvement in overall health
and quality of life attributes, and hair and coat quality (all p < .01). In summary, dogs
with IRIS-­Stage 1 CKD readily transition to renal food. Decreasing serum biomarker
concentrations and reduction in proteinuria suggest stabilized kidney function.

KEYWORDS
chronic kidney disease, diet, dogs, IRIS-Stage 1 CKD, proteinuria

1 |  BACKGROUND (Finco et al., 1999; Polzin, 2011). Chronic kidney disease is character-
ized by structural or functional abnormalities of the kidney(s) that have
Chronic kidney disease (CKD) is an irreversible disease, with progres- been present for at least 3 months or longer (Polzin, 2011). Prevalence
sive loss of renal function eventually leading to uremic crisis and death estimates for CKD in dogs have varied from 0.05% to 3.74%, although

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2017 The Authors. Journal of Animal Physiology and Animal Nutrition Published by Blackwell Verlag GmbH

J Anim Physiol Anim Nutr. 2018;102:297–307. wileyonlinelibrary.com/journal/jpn |  297


  
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298       HALL et  al

a more recent estimate of true prevalence among dogs attending UK soluble fibre, B-­complex vitamins, antioxidants, and omega-­3 fatty
primary care veterinary practices was around 0.4% (O’Neill et al., 2013). acids (Polzin, 2013). The goals of nutritional therapy are to slow pro-
Prevalence may be much higher in areas endemic for vector-­borne dis- gressive loss of kidney function, reduce clinical and biochemical con-
eases such as leishmaniasis (Cortadellas, del Palacio, Bayon, Albert, & sequences of CKD, and maintain adequate nutrition (Brown, Elliott,
Talavera, 2006). Data from IDEXX Laboratories, Inc in the USA, from Francey, Polzin, & Vaden, 2013; Polzin, 2013).
approximately 3 million dogs with SDMA concentrations measured In a double-­blinded clinical trial, dogs with spontaneous CKD
since July 2015, show that the prevalence of CKD increases with age fed therapeutic renal food experienced a median of 615 days before
(Figure 1). Approximately, 7%–10% of dogs 8–10 years of age have ele- uraemic crises developed vs. 252 days in dogs fed maintenance food
vated SDMA alone, or elevated SDMA and creatinine. Complications of (twice as long) (Jacob et al., 2002). The dogs fed renal food lived at
CKD include metabolic disorders, especially hyperphosphatemia, met- least 13 months longer than the dogs fed maintenance food (Jacob
abolic acidosis, and hyper-­ and hypokalemia, as well as dehydration, et al., 2002). It was also noted that feeding renal food to dogs with
anaemia, proteinuria, and arterial hypertension (Polzin, 2011). Chronic a lesser degree of azotemia (serum Cr concentration 2.0–3.1 mg/dl)
kidney disease occurs mostly in older dogs, and cardiac disease is a fre- delayed the onset of uremic crises by approximately 5 months (Jacob
quent comorbid disorder (O’Neill et al., 2013). et al., 2002). It is unknown if the renal function is stabilized (based
Dogs with CKD are staged according to guidelines developed on serum renal biomarker concentrations) in non-­azotemic dogs with
by the International Renal Interest Society (IRIS) and accepted by IRIS-­Stage 1 CKD with early dietary intervention.
the American and European Societies of Veterinary Nephrology and The purpose of this study was to assess the acceptance of a ther-
Urology (Polzin, 2013). The IRIS stages range from mild (IRIS-­Stage 1) apeutic renal food and its influence on the renal function biomarkers
to the most severe (IRIS-­Stage 4), and are based upon serum creatinine when fed to client-­owned dogs with IRIS-­Stage 1 CKD over a 12-­
(Cr) concentrations, the magnitude of proteinuria as measured by the month period. Prescription Diet® k/d® (Hill’s Pet Nutrition, Inc) con-
urine protein:creatinine (UPC) ratio, and blood pressure. Staging guide- tains protein and phosphorus concentrations that meet the Nutrient
lines are helpful for making diagnostic, prognostic, and therapeutic Requirements of Dogs (NRC 2006) recommended allowances. In addi-
­recommendations for CKD. tion, animal feeding tests performed by Hill’s Pet Nutrition, Inc using
Currently, nutritional management of CKD is recommended when AAFCO procedures substantiate that Prescription Diet® k/d® provides
serum Cr exceeds 1.4 mg/dl in dogs with IRIS-­Stage 2 CKD, or when complete and balanced nutrition for maintenance of adult dogs. It is an
dogs with IRIS-­Stage 1 CKD have a UPC ratio >0.5 (http://www. antioxidant enriched food that has been used to manage CKD in dogs
iris-kidney.com/pdf/treatment-recommendation-dogs.pdf). Dietary for more than 60 years (although, revisions of the original food have
interventions that might benefit renal function in non-­azotemic dogs occurred). The hypothesis of this study was that dogs would readily
with moderately reduced glomerular filtration rate (GFR), yet per- transition to renal food and concentrations of serum renal biomark-
sistently impaired urine concentrating ability or persistent proteinuria, ers (Cr, blood urea nitrogen [BUN], and symmetric dimethylarginine
e.g., IRIS-­Stage 1 CKD, have not been well studied. Typical therapeutic [SDMA]) and urinalysis parameters (urine specific gravity [USG] and
renal foods have reduced protein, phosphorus, and sodium content, UPC ratio) would remain stable across time. In addition, owner opin-
increased caloric density, increased buffering capacity, and increased ions on renal food palatability, their pet’s acceptance of renal food, and
their dog’s quality of life while consuming renal food were assessed.

2 | METHODS

2.1 | Ethics
This study protocol was reviewed and approved by the Institutional
Animal Care and Use Committee, Hill’s Pet Nutrition, Inc, Topeka, KS,
USA (Permit Numbers: 09-­488 and CP-­522). Procedures were de-
signed to avoid or minimize discomfort, distress, and pain. Dogs were
monitored for any signs of disease. If an adverse event occurred, the
dog’s health took precedence over continuation in the trial. Owners
signed an informed consent form before enrollment of their dog and
had to agree to comply with the instructions given by the veterinarian
F I G U R E   1   Data from IDEXX Laboratories in the USA, from and listed in the consent form.
approximately 3 million dogs with serum SDMA concentrations
measured since July 2015, show that the prevalence of CKD
increases with age. In addition, over two times the number of dogs 2.2 | Dogs and study design
can be diagnosed with CKD using serum SDMA concentrations as
opposed to serum creatinine concentrations alone [Colour figure can This was a prospective, longitudinal feeding study of 12-­months
be viewed at wileyonlinelibrary.com] duration utilizing a “before-­and-­after” study design. Participating
HALL et  al |
      299

clinics (44 sites) were in Kansas, Oklahoma, California, New York, none were randomized to a no-­treatment control group as we chose
Pennsylvania, Missouri, Tennessee, Georgia, Colorado, and Arizona. not to withhold a potentially beneficial treatment food.
There were a total of 43 investigators who participated in the recruit- All dogs had to have a prior client-­patient relationship with the
ment of dogs between August 14, 2009 and August 26, 2011. Two attending veterinarian and a history of partaking in a good preventive
hundred and nine dogs were screened for all stages of CKD (physical medicine program, including routine vaccinations, deworming, heart-
examination, CBC, serum biochemical profile, total T4, heartworm an- worm testing and prevention, and all recommended diagnostic testing
tigen, ACTH stimulation test, and routine urinalysis) of which 36 dogs were performed. Up to two dogs could be enrolled from one house-
were classified as IRIS-­Stage 1 CKD. Dogs with higher IRIS stages hold. During each visit, the veterinarian obtained a complete history
of CKD are not included in this report. All dogs remained with their and performed a physical examination.
owners throughout the study. Dogs were evaluated at 0, 3, 6, 9, and Veterinarians and owners were compensated for their partici-
12 months. History, physical examination forms, medication records, pation in the study. Study food was provided free of charge to pet
dietary information, and both owner and veterinarian questionnaires owners participating in the study for the duration of the study. The
were filled out electronically at every visit. Blood and urine samples veterinarians and the owners were blinded as to the sponsor of the
were obtained and submitted for analysis of selected serum analytes, study, as food was provided in bags that were marked with tracking
USG, and UPC ratio. codes but no other indications of the contents. The owners were in-
The IRIS stage of CKD was determined according to the 2006 ver- structed to maintain the renal food at room temperature in original
sion (Polzin, 2013), based on serum Cr concentration and whether food packaging.
an abnormal kidney on palpation or ultrasound, dilute urine, or ele- At each visit, owners filled out a questionnaire regarding whether
vated UPC ratio was present. Although investigators evaluated ab- their pet liked the food, their attitude while eating, and the amount
normal kidneys by palpation, radiography, or ultrasonography, imaging of food consumed (Fritsch et al., 2015). Pet owners kept daily logs
studies were not routinely performed on all dogs. Substaging of CKD during the first month to record the amount of food consumed and the
according to blood pressure measurement also was not consistently amount not eaten. They also recorded the stool appearance. Owners
performed, and therefore, not reported herein. In our study, dogs were asked to assess the overall health and quality of life using a 7
at least 2 years of age, with normal serum Cr concentrations (<1.4 point scale: (1) extreme improvement, (2) moderate improvement, (3)
mg/dl), with persistently dilute urine (USG < 1.020) without identifi- slight improvement, (4) no change, (5) slight deterioration, (6) moder-
able non-­renal cause, or persistent proteinuria of renal origin (UPC ate deterioration, and (7) extreme deterioration (Fritsch et al., 2015).
ratio >0.5) confirmed at multiple consecutive assessments (0, 1, and Owners were asked to assess the energy level and youthfulness and
3 months), were classified as IRIS-­Stage 1 CKD. To be included in the vitality using a 5 point scale: (1) greatly increased, (2) slightly increased,
study, dogs also had to have a body condition score of 2/5 or greater. (3) about the same, (4) slightly decreased, and (5) greatly decreased
Dogs were excluded if they had a major systemic disease other than (Fritsch et al., 2015). Owners were also asked to assess their dog’s
renal disease, if they could not consume dry food throughout the hair and coat quality based on lustre, amount of dandruff, texture, and
course of the study, if they had been fed a renal therapeutic food shedding using a 5-­point scale: (1) much more shiny, much less dander,
within the previous 3 months, if they had a planned surgery, were much more soft, much less shedding, (2) slightly more shiny, slightly
pregnant or likely to become pregnant during the study period, were less dander, slightly more soft, slightly less shedding, (3) about the
fractious, were in a multi-­dog household and could not be segregated, same, (4) slightly more dull, slightly more dander, slightly more course
or if they had participated in another clinical trial within the previous or brittle, slightly more shedding, and (5) much more dull, much more
6 months. dander, much more coarse or brittle, much more shedding.
Dogs could be removed from the study if the veterinarian deter-
mined that progression of kidney disease warranted additional medical
2.3 | Food composition
treatments, if a dog developed another medical condition warranting
additional medical treatments, if the dog was uncooperative with the Food composition, expressed as amount/100 g dry matter, for
study procedures, or if the owner did not comply with the study guide- Prescription Diet® k/d® is given in Table 1. Offering amounts were
lines. If an adverse event was suspected, owners were instructed to based on the presumed resting energy requirement (RER) for each
contact their veterinarian immediately. The veterinarian was required animal: RER = 70 × (ideal body weight in kg)0.75. The RER was mul-
to report details of the adverse event within 24 hr, and to conduct tiplied by a factor of 1.6 to meet maintenance energy requirements,
any necessary diagnostic tests or treatments. In the event that a dog with additional instructions to maintain body weight by increasing or
refused to eat two or more consecutive meals within a 36-­hour period, decreasing food intake.
it was dismissed from the study, and scored as rejects food.
One to two weeks after the screening visit, dogs began (day 0) tran-
2.4 | Serum and urine analyses
sitioning to renal food (Prescription Diet® k/d®, Hill’s Pet Nutrition,
Inc) and were transitioned fully over a 7-­day period. The transition was Blood was collected from each dog (after withholding food over-
accomplished by gradually mixing increasing amounts of renal food night) at each time point to assess complete blood count and serum
into grocery-­branded food. All dogs were transitioned to test food; chemistries. Serum Cr and BUN concentrations were determined by a
300       | HALL et  al

T A B L E   1   Food composition of renal fooda and NRC commercial veterinary laboratory using enzymatic colorimetric meth-
requirementsb ods. All serum SDMA concentrations were determined retrospec-

NRC requirements c tively, after the feeding trial ended, from serum stored at −70°C in
serum banks, if left over serum was available. Serum SDMA concen-
Renal Recommended
trations were measured by liquid chromatography-­mass spectrometry
Nutrient food Minimum allowance
(LC-­MS) as previously described (Hall et al., 2015), with an assay vali-
Moisture 6.88 dated in dogs (Nabity et al., 2015). The reference interval for serum
Proteind 14.67 8.0 10.0 SDMA in healthy dogs was <14 μg/dl (Rentko et al., 2013).
Fat 19.49 5.5 Urine was collected by cystocentesis at each assessment period
Energy,e kcal/100 g 4457 for routine urinalysis and UPC. Urine specimens were packaged with
Ash 4.19 frozen gel packs, and shipped overnight to the commercial laboratory
Crude fibre 2.15 (Marshfield Labs, Marshfield, WI) for immediate analysis of urine pH,
Calcium 0.75 0.20 0.40 USG, routine dipstick analysis, semi-­quantitative urine sediment anal-

Phosphorus 0.30 0.30 ysis, and UPC. Urine specific gravity was determined using a refrac-
tometer. Urine Cr concentration was used as an internal reference and
Sodium 0.21 0.03 0.08
measured with the same assay as serum Cr. Urine protein concentra-
Potassium 0.64 0.40
tions were determined using urine supernatant (benzethonium chlo-
Magnesium 0.11 0.018 0.06
ride turbidometric method). The UPC ratio calculations are reported
α-­tocopherol acetate, 720.58
as mg/dl protein: mg/dl Cr.
IU/kg
Vitamin C, mg/kg 135.31
Myristic acid [14:0] 0.18 2.5 | Statistical analysis
Palmitic acid [16:0] 3.87
Statistical analysis was performed using SAS version 9.4 (SAS
Stearic acid [18:0] 1.79 Institute, Cary, NC). For all 36 dogs, serum BUN, Cr, and SDMA con-
Arachidic acid [20:0] 0.03 centrations, UPC, and USG were analysed using a linear mixed model
LA [18:2 (n-­6)] 3.30 1.1 for repeated measures with month as fixed effect in the model (PROC
αLA [18:3 (n-­3)] 1.36 0.044 MIXED). Response variables were tested for normal distribution using
ARA [20:4 (n-­6)] 0.09 the Kolmogorov-­Smirnov test, skewness, and kurtosis measures,
EPA [20:5 (n-­3)] 0.01 0.044 and inspection of plots of the data in PROC UNIVARIATE. Based on
DHA [22:6 (n-­3)] 0.00 these tests, all data were normally distributed. p ≤ .05 was considered

SFA f
5.97
statistically significant, whereas p ≤ .10 was considered a trend. An
overall f-­test with p ≤ .10 with time as a main effect was required for
MUFAg 7.31
subsequent evaluation of a difference between times. If a difference
PUFAh 4.85
between times was evaluated, all subsequent times were compared
(n-­6) FAi 3.46
with the initial value. Data from all dogs was included until the time
(n-­3) FAj 1.40
of drop out.
(n-­6):(n-­3) ratio 2.66
The analysis was repeated in a subset of dogs (n = 20) that com-
a
Prescription Diet® k/d®, Hill’s Pet Nutrition, Inc. All analytical values are pleted all 12-­months on the feeding trial according to the protocol.
expressed as amount/100 g dry matter, with the exception of moisture. The PROC MIXED analysis was performed to evaluate the effect of
b
Nutrient Requirements of Dogs and Cats (NRC 2006).
c time on response variables within each treatment group. All data are
NRC values are expressed as amount/100 g dry matter.
d
Animal feeding tests performed by Hill’s Pet Nutrition, Inc using AAFCO reported as least square means ± SEM.
procedures substantiate that Prescription Diet® k/d® provides complete In a subset of dogs that had persistent proteinuria with UPC ratio
and balanced nutrition for maintenance of adult dogs. >0.5 at baseline (n = 16), a Chi-­Square analysis was completed to de-
e
Energy calculated using the predictive equations in the Nutrient
termine if a significant number of dogs experienced a change in pro-
Requirements of Dogs and Cats (NRC 2006).
f
Sum of the saturated fatty acids (SFA): 8:0 + 10:0 + 11:0 + 12:0 + 14:0 +  teinuria. Categorical assignment was based on increasing or decreasing
15:0 + 16:0 + 17:0 + 18:0 + 20:0 + 22:0 + 24:0. UPC ratio across time. Statistical significance was declared at p ≤ .05.
g
Sum of the monounsaturated fatty acids (MUFA): 14:1 + 15:1 + 16:1 + Owner assessments of whether their pet liked the food, their atti-
17:1 + 18:1 + 20:1 + 22:1 + 24:1.
h tude while eating, and the amount of food consumed were expressed
Sum of the polyunsaturated fatty acids (PUFA): 18:2(n-­6) + 18:3(n-­6) +
18:3(n-­3 ) + 18:4(n-­3 ) + 20:2(n-­6) + 20:3(n-­6) + 20:3(n-­3) + 20:4(n-­6) + as a percentage of the sum of all dogs at all-­time points in a particu-
20:4(n-­3 ) + 20:5(n-­3 ) + 21:5(n-­3 ) + 22:2(n-­6 ) + 22:4(n-­6 ) + 22:5(n-­6 ) lar category divided by the sum of all dogs at all-­time points. Owner
+ 22:5(n-­3) + 22:6(n-­3). ­assessment of stool appearance was expressed similarly.
i
Sum of the (n-­6) fatty acids.
j
To determine whether the owner assessments of health and
Sum of the (n-­3) fatty acids.
quality of life attributes, and owner assessments of hair and coat
HALL et  al |
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quality attributes changed over the course of the study, owner-­ ovariohysterectomized females and six neutered males. Mean body
reported scores were subtracted from 4 the “no change” response for weight was 24.6 kg (range, 3.3–47.0 kg).
overall health and quality of life attributes, or from 3 the “about the
same” response for energy level, youthfulness or vitality, and hair and
3.2 | Renal biomarkers, serum metabolites, and
coat quality attributes at each time period (3, 6, 9, and 12 months).
urinalysis parameters
A positive value indicated improvement since the previous exam pe-
riod. An overall mean response for each dog was then calculated. The Dogs consuming renal food showed decreases in serum Cr and BUN
means of individual dog’s mean values were evaluated using PROC concentrations across time (both p ≤ .01; Figure 2; Table 2) and a de-
MIXED against the null hypothesis of no change. Again, p ≤ .05 was creasing trend in serum SDMA concentration (p = .09). All serum renal
considered statistically significant whereas p ≤ .10 was considered a biomarkers (Cr, BUN, SDMA) were decreased (p ≤ .05) from baseline
trend. To evaluate whether subsequent improvements were different by 3 months, and remained decreased from baseline at 12 months in
from the initial improvement, each subsequent time period was com- dogs completing the study (n = 20). These conclusions were also true
pared with the initial response using PROC MIXED. when considering only the 20 dogs that completed the study (Table 2).
Serum albumin and phosphorus concentrations did not change signifi-
cantly across time.
3 | RESULTS
The USG showed a decreasing trend across time (p = .09; Table 2),
but not the UPC ratio (p = .88). The USG was decreased from baseline
3.1 | Dogs
at 3 and 6 months (p ≤ .05). Results were similar when the analysis was
Of the 36 dogs categorized as IRIS-­Stage 1 CKD, all had serum Cr con- limited to the 20 dogs that completed the study.
centration <1.4 mg/dl, 20 had persistently dilute urine (USG < 1.020) In a subset of dogs (n = 16) with persistent proteinuria of renal
without identifiable non-­renal cause, six had persistent proteinuria origin (UPC ratio >0.5), consuming renal food resulted in decreased
of renal origin (UPC ratio >0.5), and 10 had both persistently dilute UPC ratio in all six dogs with proteinuria compared with baseline.
urine and proteinuria. At baseline, 50% of SDMA concentrations Of the 10 dogs with persistent proteinuria of renal origin and per-
were >14 μg/dl. Thirty five dogs completed 3-­months, and 27 dogs sistently dilute urine (USG < 1.020) without identifiable non-­renal
completed 6-­months on the feeding trial. Overall, 20 dogs completed cause, consuming renal food resulted in decreased UPC ratio in six
12-­months on the feeding trial according to protocol. One dog was dogs and increased UPC ratio in four dogs. The overall effect of time
dropped out at 1 month because it refused to eat the renal food. The on food was a decrease in proteinuria in dogs with UPC ratio >0.5
most common reason for dogs consuming renal food not to complete (p = .045).
the 12-­month feeding trial was owner withdrawal after 3 months
(n = 6) and after 6 months (n = 1). The owners had originally agreed
3.3 | Success of transitioning to the renal food
to enroll their dog in a 3-­month study but the study was extended
to 12 months, so they were given the option to withdraw their dog Of the 36 IRIS-­Stage 1 CKD dogs that started the study, 35 (97.2%)
after 3 months. Additional dogs were dropped after 3 months because dogs transitioned to the renal food. One dog was dismissed after the
owners did not comply with the study protocol (n = 2). Two other dogs first month of the study because of palatability concerns.
dropped out after 6 months, one because of a ruptured spleen and he-
moabdomen (euthanized), and one because of polyuria and polydipsia
with inappropriate urination in the house. Four more dogs dropped
out after 9 months: one with prostatic carcinoma, one with pulmonary
neoplasia, one with pituitary-­dependent hyperadrenocorticism, and
one with acute on chronic renal failure (euthanized).
The IRIS-­Stage 1 CKD dogs at enrollment (n = 36) had mean age of
8.6 years, (median, 9 years; range, 2–14 years) and mean initial body
weight of 23.4 kg (range: 3.0–49.4 kg). Dog breeds included Labrador
Retriever (n = 6), mixed breeds (5, including 2 Labrador Retriever
mixed breeds), Shetland Sheepdog (3), Corgi (2), Yorkshire Terrier
(2), Australian Shepherd (2), Pomeranian (1), Golden Retriever (1),
Miniature Schnauzer (1), German Shorthaired Pointer (1), Dachshund
(1), Bloodhound (1), Jack Russell Terrier (1), Basset Hound (1), Blue F I G U R E   2   Serum SDMA (black bars) and Cr (striped bars)
Healer (1), Border Collie (1), Airedale Terrier (1), German Shepherd (1), concentrations (means ± SEM) at each visit are plotted for all dogs
(n = 35 at 3 months; n = 27 at 6 months; n = 24 at 9 months; n = 20
Cocker Spaniel (1), Soft Coated Wheaten Terrier (1), Whippet (1), and
at 12 months) at all-­time points for which data were available. Serum
Pekepoo (1).
SDMA and Cr concentrations were decreased (**p ≤ .05; *p ≤ .10)
For the 20 dogs that completed the 12-­month feeding trial, mean from initial baseline values by 3 months, and remained decreased
age was 8.2 years (median, 8 years; range, 2–14 years). There were 14 from baseline at 12 months in dogs completing the study (n = 20)
|
302       HALL et  al

T A B L E   2   Renal function biomarkers, serum metabolites, and urinalysis parameters for IRIS-­Stage 1 chronic kidney disease dogs at baseline
(initial) and after consuming renal fooda for 1, 3, 6, 9, and 12 months (mean ± SEM)

Only dogs completing the


All dogs PROC MIXED 12-­mo feeding study PROC MIXED

Number of animals, N N = 35 at 3 months p valuesb N = 20 p valuesb


N = 27 at 6 months
N = 24 at 9 months
N = 20 at 12 months
Renal function biomarkers and serum metabolites
Urea Nitrogen (mg/dl)
Initial 19.22 ± 2.64 21.00 ± 4.09
d
3 months 13.67 ± 2.19 11.55 ± 1.68d
6 months 14.74 ± 2.08d <.01 12.45 ± 1.65d <.01
9 months 17.11 ± 2.72 13.90 ± 1.89
12 months 13.47 ± 1.88d 12.60 ± 1.89d
Creatinine (mg/dl)
Initial 1.08 ± 0.02 1.07 ± 0.04
d
3 months 0.99 ± 0.02 0.94 ± 0.04d
6 months 1.02 ± 0.03e <.01 0.94 ± 0.05d <.01
e
9 months 1.01 ± 0.03 0.97 ± 0.05d
12 months 0.90 ± 0.03d 0.88 ± 0.04d
c
SDMA (μg/dl)
Initial 16.62 ± 2.10 29.42 ± 3.39
3 months 10.66 ± 0.94d 8.34 ± 0.82d
6 months 12.31 ± 1.32e .09 10.89 ± 1.07d <.01
d
9 months 11.19 ± 1.25 9.71 ± 0.91d
12 months 9.50 ± 1.64d 8.89 ± 1.13d
Albumin, mg/dl
Initial 3.23 ± 0.07 3.27 ± 0.07
3 months 3.20 ± 0.09 3.20 ± 0.09
6 months 3.16 ± 0.09 .23 3.19 ± 0.09 .23
9 months 3.16 ± 0.09 3.18 ± 0.09
12 months 3.08 ± 0.09 3.10 ± 0.09
Phosphorus, mg/dl
Initial 4.00 ± 0.15 3.92 ± 0.15
3 months 3.87 ± 0.34 .72 3.94 ± 0.34 .78
6 months 3.75 ± 0.20 3.90 ± 0.20
9 months 4.07 ± 0.18 4.10 ± 0.18
12 months 4.04 ± 0.13 4.06 ± 0.13
Urinalysis parameters
Urine specific gravity
Initial 1.022 ± 0.002 1.021 ± 0.002
d
3 months 1.016 ± 0.002 1.016 ± 0.002d
d
6 months 1.017 ± 0.002 .09 1.018 ± 0.003 .08
9 months 1.019 ± 0.002 1.019 ± 0.002
12 months 1.021 ± 0.002 1.021 ± 0.002

(Continues)
HALL et  al |
      303

T A B L E   2   (Continued)

Only dogs completing the


All dogs PROC MIXED 12-­mo feeding study PROC MIXED

Urine Protein:Cr Ratio


Initial 1.19 ± 0.35 1.07 ± 0.35
3 months 1.51 ± 0.36 1.03 ± 0.36
6 months 1.48 ± 0.40 .88 0.96 ± 0.40 .34
9 months 1.13 ± 0.43 1.21 ± 0.43
12 months 1.00 ± 0.48 0.92 ± 0.48
a ® ®
Prescription Diet k/d , Hill’s Pet Nutrition, Inc.
b
p values are shown for main effect of time.
c
All serum SDMA concentrations were determined retrospectively after the feeding trial ended, from serum stored at −70°C in serum banks. Serum was
not available for all dogs.
d
Means within a column are different from the initial at p ≤ .05.
e
Means within a column are different from the initial at p ≤ .10.

F I G U R E   4   Owners’ assessment of stool appearance at 3, 6, 9, and


12 months after transition to renal food (Prescription Diet® k/d®).
Overall percentages were calculated for all dogs at all visits

dividing by the sum of all dogs at all-­time points with all possi-
ble results, owners reported that their dogs moderately or ex-
tremely liked the renal food 88% of the time, ate most or all of
the food 84% of the time, and 76% of the time were moderately
or extremely enthusiastic while eating (Figure 3). Owners rarely
reported their dog as disliking the food (6%), not at all enthusi-
astic while eating it (8%), or frequently refusing to eat the food
(0%). Stool quality was excellent, with only 7% semi-­formed stools
being reported (Figure 4).

F I G U R E   3   Owners’ assessment of whether their pet liked renal


3.5 | Owner assessment of overall health and
food (Prescription Diet® k/d®), their attitude while eating, and the quality of life attributes
amount of food consumed recorded at 3, 6, 9, and 12 months.
At each visit, owners were asked to rate how overall health, quality of
Overall percentages were calculated for all dogs at all visits
life, energy level, and youthfulness and vitality had changed since the
previous visit. These parameters were rated on a 5 or 7 point scale,
with a score of “1” being the most favourable and a score of “5” or
3.4 | Owner assessment of food consumption and
“7” being the most unfavourable. The middle score represented “no
stool quality
change” or “about the same” (Table 3). All health and quality of life
During each exam period, owners were asked to evaluate whether attributes were significantly (p ≤ .05) or tended to be (p ≤ .10) im-
their pet liked the food, their attitude while eating, about food proved across time. There was significant initial improvement noted at
consumption, and to assess the stool quality. Summing all dogs 3 months (p ≤ .05) and subsequent improvement noted at 12 months
at all-­time points for specific results in a particular category and (p ≤ .10).
|
304       HALL et  al

T A B L E   3   Owner assessment of health, quality of life, hair, and coat quality attributes. Owner-­reported scores were subtracted from the “no
change” or from the “about the same” responses in each category at each time period (3, 6, 9, and 12 months). A positive value indicated the
improvement since the previous exam period. An overall mean response for each dog was calculated based on the amount of time each dog
was enrolled in the study

Questions Scale range Mean ± SEM p-­valuea

Health and quality of life attributes


Since the last exam, how has your dog’s overall health changed?b 1–7 0.65 ± 0.36 .08
Since the last exam, how has the quality of life for your dog changed?b 1–7 0.46 ± 0.27 .10
c
Since the last exam, have you observed a change in your dog’s energy level? 1–5 0.47 ± 0.25 .06
Since the last exam, have you observed a change in your dog’s youthfulness or vitality?c 1–5 0.55 ± 0.24 .02
d
Ʃ Health and quality of life attributes above 0.53 ± 0.21 <.01
Hair and coat quality
Since the last exam, have you observed a change in the lustre of your dog’s coat?e 1–5 0.48 ± 0.27 .08
Since the last exam, have you observed a change in the amount of dandruff on your dog’s coat?e 1–5 0.35 ± 0.13 <.01
Since the last exam, have you observed a change in the texture of your dog’s coat?e 1–5 0.40 ± 0.20 .05
Since the last exam, have you observed a change in the amount of hair that your dog has shed?e 1–5 0.34 ± 0.19 .08
d
Ʃ Hair and coat quality attributes above 0.39 ± 0.13 <.01
a
The means of individual dog’s mean values were evaluated using PROC MIXED against the null hypothesis of no change. A p ≤ .05 was considered statisti-
cally significant while a p ≤ .10 was considered a trend.
b
Owners were asked to assess overall health and quality of life using a 7 point scale: (1) extreme improvement, (2) moderate improvement, (3) slight
­improvement, (4) no change, (5) slight deterioration, (6) moderate deterioration, and (7) extreme deterioration.
c
Owners were asked to assess energy level and youthfulness and vitality using a 5 point scale: (1) greatly increased, (2) slightly increased, (3) about the same,
(4) slightly decreased, and (5) greatly decreased.
d
An overall mean response for all health and quality of life attributes or all hair and coat quality attributes were evaluated using PROC MIXED against the
null hypothesis of no change. A p ≤ .05 was considered statistically significant while a p ≤ .10 was considered a trend.
e
Owners were also asked to assess their dog’s hair and coat quality based on lustre, amount of dandruff, texture, and shedding using a 5-­point scale: (1)
much more shiny, much less dander, much more soft, much less shedding, (2) slightly more shiny, slightly less dander, slightly more soft, slightly less shed-
ding, (3) about the same, (4) slightly more dull, slightly more dander, slightly more course or brittle, slightly more shedding, and (5) much more dull, much
more dander, much more coarse or brittle, much more shedding.

that renal food delayed the onset of uremic crises and increased me-
3.6 | Owner assessment of hair and coat
dian survival times in azotemic dogs with spontaneous CKD. Based on
quality attributes
the current study, we suggest that renal food also stabilizes or slows
At each exam, owners assessed change in hair and coat quality at- disease progression in non-­azotemic dogs with IRIS-­Stage 1 CKD.
tributes since the previous visit. Coat lustre, amount of dandruff, Prescription Diet® k/d® (Hill’s Pet Nutrition, Inc) contains protein
coat texture, and amount of shedding were rated on a 5-­point scale, (14.67 g/100 g dry matter) and phosphorus (0.30 g/100 g dry mat-
with a score of “1” being the most favourable and a score of “5” ter) concentrations that meet the Nutrient Requirements of Dogs
being the least favourable. The middle score represented “about the (NRC 2006) recommended allowances. We previously reported that
same” (Table 3). All hair and coat quality attributes were significantly client-­owned geriatric dogs with increased serum SDMA concentra-
(p ≤ .05) or tended to be (p ≤ .10) improved across time. Although tions (non-­azotemic, IRIS-­Stage I CKD) had decreased serum SDMA
there was significant initial improvement noted at 3 months (p ≤ .05), and Cr concentrations after feeding a different test food for 6 months
there was no further improvement, nor deterioration, noted at (protein, 23.58 g/100 g dry matter; phosphorus, 0.74 g/100 g dry
12 months. matter; and functional ingredients designed to promote healthy
­aeging) (Hall, MacLeay, et al., 2016). Both the food fed in this study
(Prescription Diet® k/d®) and the food fed in the former study (test
4 |  DISCUSSION food) had lower protein and phosphorus concentrations than industry
averages (Debraekeleer, Gross, & Zicker, 2010). In the Debraekeleer
Feeding client-­owned dogs with IRIS-­Stage 1 CKD Prescription report, protein and phosphorus concentrations for 65 canine foods
Diet® k/d® over a 12-­month period resulted in the stabilization of sold for growth, reproduction, young adult dogs, and mature adult
kidney function based on decreased biomarker concentrations. All dogs were 26.6 g/100 g dry matter average protein concentration and
serum renal biomarkers (Cr, BUN, SDMA) decreased from baseline to 0.98 g/100 g dry matter average phosphorus concentration. In both
3 months (n = 35), and remained decreased from baseline concentra- our studies, renal foods were lower in protein and phosphorus than
tions at 12 months in dogs completing the study (n = 20). These results industry averages, but adequate for Nutrient Requirements of Dogs
expand the findings of Jacob et al. (Jacob et al., 2002) who showed (NRC 2006) recommended allowances. However, benefits of renal
HALL et  al |
      305

food were unlikely related solely to protein and phosphorus concen- et al., 2015). Nonetheless, serum Cr concentrations were significantly
trations. Traditional nutritional studies have focused on individual nu- decreased by 3 months, and continued to decrease over the 12-­month
trients or foods, but their additive or interactive influences may be feeding period in dogs completing the study.
better observed when complete diets or several nutritional interven- We recently showed in dogs that serum SDMA correlates with
tions in combination are studied in healthy aeging trials (Lin, Fung, Hu, GFR (Hall, Yerramilli, Obare, Yerramilli, Panickar, et al., 2016) and is not
& Curhan, 2011). Thus, it is likely that the combination of high-­quality, affected by changes in muscle mass with aeging (Hall et al., 2015). In
adequate, but lower than the industry average protein concentrations, addition, serum SDMA concentrations increase earlier than the serum
and adequate, but lower than the industry average phosphorus con- Cr concentrations in dogs with CKD (Hall, Yerramilli, Obare, Yerramilli,
centrations, along with antioxidant and (n-­3) fatty acid enrichment all Almes, et al., 2016). SDMA has been shown to be an accurate and
contributed to improving renal function in these studies. precise biomarker for calculating GFR in humans (Bode-­Boger et al.,
In humans, the decline in renal function that occurs in aeging and 2006), as well as a more sensitive biomarker than serum Cr for as-
CKD populations may be linked to increased levels of oxidative stress sessing renal dysfunction (Dixon, Lane, Dalton, MacPhee, & Philips,
and inflammation (Vlassara et al., 2009). Food is a major source of ox- 2013). In our study, decreasing serum SDMA concentrations sug-
idants, and diets can be modified to effect changes in oxidant burden gested improvement in GFR, i.e., stabilization and compensatory renal
(Vlassara et al., 2009). A pro-­inflammatory diet, based on the putative function. Importantly, we were able to detect this effect by monitoring
pro-­inflammatory and anti-­inflammatory effects of nutrients, vitamins, serum SDMA concentrations, which were significantly decreased by
and trace elements, is associated with the systemic inflammation as 3 months, and remained decreased at 12 months in the subset of 20
well as with reduced kidney function (Xu et al., 2015). Thus, inflamma- dogs completing the 12-­month feeding study.
tion may be one of the pathways through which diet can affect kidney In addition to the improvement in GFR, the reason that BUN con-
function (Xu et al., 2015). centrations decreased after one month in this study was because di-
Prescription Diet® k/d® contains higher amounts of alpha lino- etary protein concentrations decreased from higher concentrations in
lenic acid [18:3 (n-­3)] compared with most commercially available pre-­trial foods to 14.67% in Prescription Diet® k/d®. Diets formulated
foods. We have previously shown that the serum concentrations of for managing azotemic dogs with renal disease typically contain 14%–
(n-­3) fatty acids, including eicosapentaenoic acid (EPA) and docosa- 20% protein (Forrester, Adams, & Allen, 2010), to control signs asso-
hexaenoic acid (DHA), are increased in dogs consuming Prescription ciated with uraemia and accumulated waste products derived from
® ®
Diet k/d for 6 months (initial EPA, 1.33 ± 0.10 mg/dl, 6 months protein catabolism. We and others have previously reported that foods
EPA, 1.68 ± 0.10 mg/dl; initial DHA, 1.66 ± 0.10 mg/dl, 6 months containing 14% protein provide adequate protein for the maintenance
DHA, 3.51 ± 0.23 mg/dl) (Hall & Jewell, 2012). These polyunsatu- of adult dogs (Hall & Jewell, 2012; Jacob et al., 2002). Indeed, serum
rated fatty acids (PUFA) subsequently influence the physical nature albumin concentrations in this study did not change across time.
of cell membranes and membrane protein-­mediated responses, in- No change was noted in UPC ratio across time when consider-
cluding lipid-­mediator generation, cell signalling, and gene expres- ing all 35 dogs, or dogs completing the 12-­month feeding study.
sion in many different cell types (Calder & Yaqoob, 2009). The (n-­3) However, in a subset of 16 dogs with persistent proteinuria of renal
PUFA and lysophospholipids (Hall, Brockman, & Jewell, 2011) and origin, consuming renal food resulted in decreased UPC ratios in 12
eicosanoids derived from EPA and DHA may protect against exces- dogs compared with baseline UPC ratios. This finding suggests that
sive inflammatory reactions. Previous studies in dogs with a remnant renal function had stabilized. Previous studies in dogs with a remnant
kidney model of CKD have shown that feeding foods enriched in kidney model of CKD have shown that feeding food enriched by 15%
(n-­3) PUFA also attenuates glomerular hypertension, tubulointer- in (n-­3) PUFA attenuates proteinuria (Brown et al., 1998, 2000). In hu-
stitial fibrosis, glomerulosclerosis, and limits the production of pro-­ mans, a meta-­analysis on the use of long-­chain (n-­3) PUFA supple-
inflammatory eicosanoid mediators such as PGE2 and TxA1 (Brown ments showed decreased urine protein excretion (Miller et al., 2009).
et al., 1998, 2000). Proteinuria is a negative prognostic indicator for dogs with declining
Measurement of GFR is the gold standard method for estimating kidney function (Vaden & Elliott, 2016). Thus, decreased UPC ratios in
the renal function and staging kidney disease (Von Hendy-­Willson & 12 of 16 dogs with proteinuria was a positive finding.
Pressler, 2011). Because measuring GFR is technically cumbersome Overall, dogs did not show an increase in urine concentrating
and expensive, serum Cr concentration has been the standard surro- ability during the 12-­month feeding period, rather USG was further
gate for GFR (Polzin, 2013). However, serum Cr has limitations as a decreased by 3 and 6 months compared with baseline. However, by
biomarker for kidney function, most notably insensitivity because it 12 months, USG was no longer different from baseline in dogs com-
remains in the normal reference interval (with a flat slope over much of pleting the study. Decreasing serum SDMA concentrations suggested
the GFR range) until GFR is reduced approximately 75% (Finco, Brown, improvement in GFR, reflecting stabilization and compensatory renal
Vaden, & Ferguson, 1995; Hall, Yerramilli, Obare, Yerramilli, Almes, function at the filtration level. At the renal tubular level, loss of con-
et al., 2016). Other non-­renal factors also influence serum Cr, includ- centrating ability may be one of the earliest indicators of kidney
ing endogenous production by muscle, such that muscle mass, breed, dysfunction and it usually occurs when two-­thirds of nephrons are
and sex influence serum Cr concentration. Because older animals have non-­functional. The renal interstitial osmolarity gradient is decreased
less muscle mass, age indirectly affects serum Cr concentration (Hall because of increased urine flow per nephron or because of an inability
|
306       HALL et  al

to establish and maintain the medullary concentration gradient. In this feeding a renal diet to dogs with IRIS-­Stage 1 CKD should be consid-
study, we did not see improvement of tubular concentrating ability. ered the standard of care (Polzin, 2013).
Limitations of this study include lack of GFR determinations, lack
of a true control group that did not receive renal food, and high drop-
AC KNOW L ED G EM ENTS
out rate. Because this study was performed in client-­owned animals,
the types of assessments we could perform were limited. Rather The authors thank Dr. Roberta Relford and Dr. Donald J McCrann,
than determining GFR in client-­owned dogs by ­iohexol plasma clear- IDEXX Laboratories, Inc, Westbrook, ME, USA for the data analysis in
ance (Von Hendy-­Willson & Pressler, 2011), we serially assessed generating Figure 1.
serum SDMA, Cr, and BUN concentrations across time as surro-
gate biomarkers for GFR. For ethical reasons, we did not withhold
ET HI C S AP P ROVAL AND CO NS ENT TO PART I C I PAT E
dietary treatment from any dog. Thus, we used before-­and-­after
measurements in a longitudinal study design to assess the response See “Methods, Ethics” section.
to renal food, recognizing that outcomes could be related to other
factors, such as natural progression of disease or stabilization re-
CO NS ENT FO R P U B L I C AT I O N
gardless of food fed. Thus, conclusions are limited to the study pe-
riod of 12 months, and controlled clinical trials of longer duration are Not applicable.
needed. Recognizing these limitations, decreases in serum Cr, BUN,
and SDMA in these IRIS-­Stage 1 CKD dogs over a 12-­month period
AVAI L AB I L I T Y O F DATA AND M AT ER I AL
suggest stabilization of CKD. Although not as rigorous as a blinded,
randomized, placebo-­controlled feeding trial, serum biomarker con- All relevant data are within the paper.
centrations in this before-­and-­after study design are not subject to
owner or operator bias.
CO NFL I C T O F I NT ER ES T
It is usually recommended that a gradual switch from grocery-­
branded food to renal food be made over a 7 to 10-­day period (Polzin, The authors of this manuscript have the following competing inter-
2013). Of client-­owned dogs with IRIS-­Stage 1 CKD, all but one (97%) ests: two of the authors (DAF and DEJ) have an affiliation to the com-
transitioned to the renal food (Prescription Diet® k/d®). Owners re- mercial funders of this research, as employees of Hill’s Pet Nutrition,
ported that renal food was generally well liked (88%), dogs ate enthu- Inc. The work presented in this study was funded by and performed at
siastically (76%), and dogs consumed most or all of the food offered the Pet Nutrition Center, Hill’s Pet Nutrition, Inc, Topeka, KS. http://
(84%). Pet owners also reported that stool quality was very good in www.hillspet.com/our-company.html). Three of the authors (MY, EO,
93% of dogs, with only 7% of dogs producing semi-­formed faeces. and MY) have an affiliation to a commercial company, as employees
Overall health and quality of life attributes and hair and coat qual- of IDEXX Laboratories, Inc, that holds a patent on the ELISA meth-
ity attributes significantly improved. The most improvement in hair and odology for measuring SDMA concentration. (http://www.idexx.
coat quality was noted at 3 months with no further improvement, nor com/view/xhtml/en_us/corporate/home.jsf). The patent no. is United
deterioration, assessed thereafter. However, there was significant on- States Patent No. US 481,690 B2; Date: July 9, 2013 Murthy et al.,
going improvement noted in overall health and quality of life attributes Methods for Detecting Symmetrical Dimethylarginine. This does not
at 12-­months, similar to the improvement noted in renal biomarkers alter our adherence to policies on sharing data and materials. Jean A.
over the 12-­month feeding period. It is possible that increased (n-­3) Hall has received research grant support from IDEXX Laboratories, Inc
PUFA content in renal food resulted in a faster positive response in in the past 12 months.
hair and coat quality attributes, yet this response was sustained. The
changes in overall health and quality of life attributes were more grad-
AU T HO R S ’ CO NT R I B U T I O NS
ual, yet consistent with the improvement in serum renal biomarker
concentrations. The UPC ratio and USG did not change over time. Conceived and designed the experiments: JAH, DAF, Murthy Y, DEJ.
These results suggest that consumption of renal food actually stabi- Performed the experiments: DAF, Maha Y, EO. Analysed the data: JAH,
lized or slowed the progression of CKD. DAF, Murthy Y, DEJ. Contributed reagents/materials/analysis tools: JAH,
DAF, Maha Y, EO, Murthy Y, DEJ. Wrote the paper: JAH, DAF, Murthy
Y, DEJ.
5 |  CONCLUSIONS
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