Dietary Nutrient Evaluations in a Cohort of Dogs with Aminoaciduric Canine Hypoaminoacidemic Hepatopathy Syndrome Inform Dietary Targets for Protein, Fat, Sodium, and Calcium
1
Loftus Laboratory, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
2
Comparative Hepatobiliary and Intestinal Research Program (CHIRP), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, 601 Vernon L. Tharp St., Columbus, OH 43210, USA
3
The Schwarzman Animal Medical Center, 510 East 62nd Street, New York, NY 10065, USA
4
Nutrition Service, Red Bank Veterinary Hospitals, Tinton Falls, NJ 07724, USA
5
Veterinary Communication Manager, Nestlé Purina PetCare, Checkerboard Square, St. Louis, MO 63164, USA
6
BluePearl Specialty and Emergency Pet Hospital, 3000 Busch Lake Blvd, Tampa, FL 33614, USA
*
Author to whom correspondence should be addressed.
Pets 2024, 1(3), 216-227; https://doi.org/10.3390/pets1030016
Submission received: 15 August 2024
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Revised: 23 September 2024
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Accepted: 25 September 2024
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Published: 27 September 2024
(This article belongs to the Topic Research on Companion Animal Nutrition)
Abstract
:Aminoaciduric canine hypoaminoacidemic hepatopathy syndrome (ACHES) is a rare syndrome affecting dogs. Nutritional management is a pillar of optimal treatment. Currently, there are no specific published data to inform dietary nutrient composition selections for treating affected dogs. Thus, our goal was to establish nutrient targets for the dietary management of ACHES by comparing nutrient profiles of commercial and home-cooked diets fed to dogs after diagnosis and determine if different nutrient inclusions were associated with survival. This retrospective cohort study evaluated nutrient profiles of commercial diets (n = 10) and home-cooked diets (n = 8) fed to dogs with ACHES. Associations between dietary nutrient inclusions and survival duration were determined using Cox proportional hazard analysis. Home-cooked diets were significantly (p < 0.001) higher in dietary protein and several amino acids than commercial diets. Risks of death were significantly (p < 0.05) lower with increasing dietary protein (hazard ratio 0.92 [CI 0.82–1.0]) and sodium (hazard ratio 0.02 [CI < 0.01–0.38]) and higher for dietary fat (hazard ratios 1.15 [CI 1.02–1.37]). An increased risk of death with increasing dietary calcium did not achieve significance (p = 0.067, hazard ratio 9.92 [CI 1.02–201.0]). These results were used to recommend target dietary nutrient ranges, in g/1000 kcal, of 90–130 for protein, 20–40 for fat, 0.7–1.8 for sodium, and 1.0–2.8 for calcium for dietary ACHES management.
1. Introduction
Aminoaciduric canine hypoaminoacidemic hepatopathy syndrome (ACHES) is a recently defined term that describes dogs with the metabolic syndrome of hepatocutaneous-associated hepatopathy (HCH), hypoaminoacidemia, and aminoaciduria with or without the presence of superficial necrolytic dermatitis (SND) [1]. Historically, this condition has often been referred to as hepatocutaneous syndrome (HCS) when HCH occurs in concert with SND and was first reported in the English-language veterinary literature as a dermatopathy associated with diabetes mellitus (DM) in 1986 [2]. Recently, progression to the later stage disease state has been associated with the development of SND. However, HCH can occur earlier in the disease process before SND develops [1]. To assist in diagnosis, recent descriptions of ACHES biomarkers based on hypoaminoacidemia and aminoaciduria have been demonstrated [1]. In particular, lower plasma concentrations of 1-methylhistidine and cystathionine were the best diagnostic biomarkers, with increased urine concentrations of lysine and methionine being the best urine amino acid biomarkers [1]. Although the etiopathogenesis of ACHES remains obscure, dysregulation of hormones involved in nutrient homeostasis has been implicated. Lower concentrations of glucagon and glucagon-like peptide-1 (GLP-1), hormones involved in glucose and amino acid homeostasis, have recently been reported in lower levels in dogs with ACHES that were prospectively compared to healthy control dogs [3].
Proposed treatment recommendations for ACHES focus on three central pillars: parenteral infusions, enteral supplements, and home-cooked diets [4]. Parenteral infusions are administered via peripheral or central intravenous catheterization [5] and include amino acid (AA) solutions, which have long been considered the gold standard of therapy [6]. More recently, parenteral lipid solution administration was described in a case report as a potentially beneficial adjunct treatment [7]. Enteral supplements aim to restore depleted AAs vital for collagen synthesis (lysine, proline), support the urea cycle (arginine and ornithine), and promote glutathione synthesis (cysteine, glycine, SAMe) [4]. However, in investigating patient outcomes with ACHES, the single independent treatment variable with the greatest impact on patient survival was feeding a home-cooked diet following diagnosis compared to feeding a commercially available diet [4]. Notably, the survival advantage associated with home-cooked diets persisted when dogs surviving < 30 days were excluded. Similarly, case report evidence also describes the long-term survival of a patient with HCS treated with AA infusions and a balanced home-cooked diet [8]. Despite these reports, optimal evidence-based nutrient targets for the dietary management of ACHES still need to be improved, and current recommendations are based primarily on clinical experience alone without specific dietary nutrient composition targets published in the existing body of literature.
Our primary goal was to propose dietary nutrient targets for dogs with ACHES based on a retrospective dietary analysis. Given that a clear survival benefit was demonstrated in ACHES patients fed a home-cooked diet after diagnosis [4], our approach to achieving this goal was to (a) compare nutrient profiles of home-cooked and commercial diets fed after ACHES diagnosis and (b) identify possible dietary nutrients in home-cooked and commercial diets positively or negatively associated with survival in ACHES patients.
2. Materials and Methods
Study Design—Retrospective Cohort Study of 18 Client-Owned Dogs
Case selection criteria: Enrolment of all cases complied with the Cornell University Institutional Animal Care and Use Committee (2017-0094). Diagnostic criteria to determine ACHES cases as previously described were applied [1,4]. All cases in this study were derived from a previously published cohort investigating aminoaciduric canine hypoaminoacidemic hepatopathy syndrome (ACHES) between 2014 and 2020 [4]. We chose to derive cases from this cohort for two reasons. First, relationships between treatments and outcomes had already been conducted, obviating the need to repeat them. Secondly, since publishing the treatment and outcomes of that cohort, in the authors’ experience, nearly all owners of dogs afflicted with ACHES now choose to pursue home-cooked diets for their pets, limiting our access to new ACHES cases fed commercial diets. One of two authors (JPL or MGC) provided nutritional recommendations to all primary veterinarians or clients, including a high-protein commercial diet (e.g., a high-protein veterinary therapeutic mobility diet or an over-the-counter performance diet) if a home-cooked diet was declined.
Disease-specific survival data from the original cohort were used in this study, and dogs that died or were euthanized for reasons unrelated to ACHES were censored for survival analyses [4]. Dietary data from these cases were then extracted from the medical record and verified with owners or primary veterinarians as needed, including diet information fed at the time of diagnosis, diet information immediately following diagnosis, and dietary changes during ongoing medical management of the condition. Whether or not a patient received amino acid infusion(s) as part of treatment was recorded. We did not include other management strategies (lipid infusions and additional enteral supplements) in this study as those were previously assessed in the parent cohort [4].
Diet information: Dietary assessment was performed retrospectively from the available medical records of cases. The assessed information included any specific commercial diet formulation and any home-cooked diet fed during the study period. Dogs exclusively (as a primary diet, treats were not an exclusion criterion as they were poorly recorded, and no cases were estimated to be fed in an amount > 10% of total caloric intake) fed a commercial diet following diagnosis of ACHES were assessed in the commercial diet group. In contrast, dogs exclusively fed a home-cooked diet were assessed in the home-cooked diet group. No cases were fed a home-cooked diet before a diagnosis of ACHES within the study cohort. Cases were excluded if an accurate nutrient profile could not be assembled for a case or if their diet was changed at diagnosis and their survival post-diagnosis was <30 days. Reasons for exclusion included feeding multiple diets without specific proportions recorded or if the brand and formula of food were not recorded. Nutrient profiles were obtained from the companies of commercial diets fed during the study period. Given the retrospective nature of this study, nutrient profiles (list of requested nutrients in Table 2) were requested from the diet manufacturers for the specific diets from the year the diets were fed. However, in several instances, diet information from the specific year within the study period was not available for review by the company; instead, 2016 product guides were used. Home-cooked diets were formulated using commercial software (Balance.IT Autobalancer®) for all dogs except one by one of the authors (JPL or MGC). The same software generated nutrient profiles for all home-cooked diets. The reported dietary requirements are from the National Research Council’s nutrient requirements for the maintenance of adult dogs [9].
Key nutrient range development: Nutrients with hazard ratios < or >1 were sorted individually from lowest inclusion to highest inclusion to identify a “breakpoint” where the survival trend was greater than 359–557 days (range between all-cause and disease-specific median survival times previously reported [4]), as we considered this the optimal target survival time range. We then cross-referenced this approach with nutrient ranges of the commercial vs. home-cooked diets to identify rational clinical recommendations for nutrient targets that were within the National Research Council’s nutrient requirement guidelines.
Statistical analyses: We report categorical data as proportions and continuous data as medians and ranges. Fisher’s exact test compared the number of dogs that did or did not receive amino acid infusions between home-cooked and commercial diet groups. The Mann–Whitney test compared the ages and weights of dogs fed commercial vs. home-cooked diets. Multiple Mann–Whitney tests were conducted comparing nutrient inclusions between commercial diets and home-cooked diets. The false discovery rate, set at 1%, was used to control for multiple comparisons using a two-stage setup (Benjamini, Krieger, and Yekutieli method). Cox proportional-hazards regression was performed to assess relationships between dietary nutrient inclusions that were available for all dogs (protein, total dietary fat, vitamin E, calcium, potassium, and sodium in g/1000 kcal as continuous variables) and disease-specific survival duration. We report a one-tailed hypothesis p value for protein as we predicted higher protein would be associated with a lower risk of death. However, two-tailed p values for all other nutrients were reported as we did not have an a priori expectation for increased or decreased risk. For validation of nutrient ranges, the corresponding cutoffs for protein, fat, sodium, and calcium were dichotomized with the comparator category (i.e., the group with the lower risk of death based on initial analysis) assigned a value of “0” and the group with higher risk assigned a value of “1”. One-tailed hypotheses were assumed for validation testing, and corresponding p values are reported. Parameter linearity was confirmed by evaluating deviance vs. hazard ratio plots and ensuring the data centered around a deviance of zero. Commercial software (Prism 9.0 or later, GraphPad, San Diego, CA, USA) computed the statistical analyses and generated corresponding graphs. A p value < 0.05 established significance.
3. Results
3.1. Patient Demographics
The patients included in this study represent a subset of an original patient cohort previously published [1,4] that contained sufficient dietary data for analysis in the present study (Table 1). These patients received either a commercial diet (n = 10) or a home-cooked diet (n = 8) following diagnosis of ACHES. There were no differences in age (commercial median = 10.5 y (7–14 y); home-cooked median = 10 y (8–14 y)) or weight (commercial median = 10.0 kg (2.3–35 kg); home-cooked median = 11.55 kg (4.8–38 kg)) between diet groups. There was no difference (p = 1.0) in the number of dogs that did or did not receive amino acid infusions between the home-cooked and commercial diet groups.
3.2. Home-Cooked Diets Were Substantially Higher in Protein
The protein content in home-cooked diets was substantially higher than commercially available diets, with the minimum value of protein in any home-cooked diet (88.9 g/1000 kcal) almost matching the maximum protein value (90 g/1000 kcal) of any commercially available diet (Table 2). The protein content was significantly greater in home-cooked diets when the mean rank difference was compared to the commercially available diets (Figure 1). When individual amino acids contributing to this protein content difference were assessed, all measured amino acids except tryptophan were significantly more abundant in home-cooked diets (Figure 1). Aside from protein and amino acids, the only other nutrient significantly increased in home-cooked diets was vitamin K (Figure 1). Nutrients significantly higher in commercially available diets than in home-cooked diets were vitamin E, iodine, manganese, copper, calcium, and phosphorus (Figure 1).
3.3. Dietary Inclusions of Several Nutrients Were Associated with Survival Times
A Cox proportional hazard ratio was utilized to determine if nutrient inclusions, irrespective of diet type, were associated with the survival duration of the individual patients assessed (Table 3). As all nutrient value variables were continuous data, the hazard ratio indicates the estimated proportional risk of death for each increase of one unit for each variable. Higher dietary protein was associated with a modest decreased risk of death, with an estimated hazard ratio of approximately 0.9, which can also be interpreted as a 10% reduction in risk of death for every 1 g/1000 kcal of dietary protein. Higher dietary sodium was associated with a substantially decreased risk of death, with a hazard ratio of 0.02, estimating an approximately five-fold reduced risk for every increase of 0.1 g/1000 kcal of dietary sodium. To better interpret this result, we scrutinized the sodium values vis-à-vis survival status. Notably, four dogs were fed diets with sodium less than 0.7 g/1000 kcal. All four of those dogs had ACHES-related deaths of 8, 168, 214, and 557 days. Thus, it is more appropriate to clinically interpret a higher risk of death associated with diets lower in sodium. Nutrients associated with increased risk of death were higher calcium and total dietary fat. Higher dietary calcium was associated with nearly a 10-fold higher risk of death; however, the wide CI indicates a high degree of imprecision in the model. Dietary inclusions of vitamin E and potassium were not associated with mortality risk.
3.4. Dietary Targets
Dietary protein, fat, sodium, and calcium were further scrutinized to identify rational dietary inclusion target ranges for managing dogs with ACHES (Figure 2). The dietary target ranges include a value based on the survival cutpoints and other values based on ranges fed to dogs in this study or dietary nutrient requirements. We validated these cutoffs by conducting two rounds of Cox proportional hazards analysis, where the cutoff for dietary sodium dichotomization was decreased from 0.8 to 0.7 in the second round (Table 4). This approach highlighted protein, fat, and sodium as the most reliable associations with survival, where the estimated risks of death were 21× higher with diets < 90 g/kcal protein, 26× higher for diets with ≥40 g/kcal fat, and 13× higher for diets with <0.7 g/1000 kcal sodium. While these cutoffs introduced less precision in the model, even using the most conservative estimates (the lower 95 CI values), the increased risks of death were 80% higher with diets < 90 g/kcal protein, 60% higher for diets with ≥40 g/kcal fat, and 50% higher for diets with <0.7 g/1000 kcal sodium. Adjustments in calcium inclusions in the validation process resulted in concerns for model overfitting (i.e., relative risks were over five figures, and CIs could not be estimated), so the original range was maintained for the final recommendation range, which did not achieve significance. Notably, we still provide a conservative recommendation for a target range of dietary calcium based on survival trends that did not achieve significance.
A hazard ratio < 1.0 indicates a corresponding proportional reduced risk of death/euthanasia (increased survival) for the indicated nutrient inclusions.
A hazard ratio > 1.0 indicates a proportional increased risk of death/euthanasia (decreased survival) for the indicated nutrient inclusions.
4. Discussion
We conducted a retrospective cohort study of 18 dogs with aminoaciduric hypoaminoacidemic hepatopathy syndrome (ACHES), comparing the nutrient profiles of dogs fed home-cooked or commercially available diets. We found dogs fed a home-cooked diet received a nutrient profile containing significantly greater protein content than the commercially available diets in our study. Furthermore, higher total dietary protein was associated with a decreased risk of death for dogs with ACHES.
A significantly longer median survival time and lower relative risk of death for dogs with ACHES fed home-cooked vs. commercial diets have been previously demonstrated [4]. The present analysis advances the previous finding by identifying protein as a nutrient in significantly greater amounts in home-cooked diets that were also associated with a survival benefit. Unexpectedly, sodium was also identified as a nutrient that was statistically associated with a survival benefit, though it did not significantly differ between home-cooked and commercially available diets. In contrast, both total fat and calcium (although not achieving statistical significance at p < 0.05) were identified as nutrients associated with decreased survival duration for dogs with ACHES. Calcium was found in significantly greater amounts in the commercially available diets than in home-cooked diets, while total fat content did not differ substantially between groups. Additionally, while this study focused on associations with individual nutrients that differed between home-cooked and commercial diets, other characteristics of home-cooked diets may be beneficial. This includes increased palatability that may contribute to sustained dietary intake and, therefore, a favorable energy balance for a population of generally older patients where decreased energy intake is known to impact the development of malnutrition, loss of lean body mass, and shorter survival. Unfortunately, the retrospective nature of this study precluded the availability of reliable and longitudinal body and muscle condition scoring for dogs in this study.
Still, from our cohort, several dogs fed commercial diets experienced survival of over one year, making it unlikely that their intake was substantially lower than those fed home-cooked diets. Moreover, a recent metabolomic analysis of dogs with ACHES identified several metabolites that could be linked to environmental or dietary exposures or the microbiome, some of which could be related to differences in home-cooked and commercial diets [10]. Future studies evaluating home-cooked and commercial diets with similar nutrient profiles are required to determine if the form of food impacts outcome or if outcomes are primarily driven by the more favorable nutrient profiles achievable in home-cooked diets. In other words, commercial diets with similar nutrient targets may be as appropriate for dogs with ACHES as home-cooked diets. It is also important to note that because the relationship between nutrient inclusions and patient survival in this study was agnostic to diet type, the nutrient targets should be considered the same for home-cooked or commercial diets for dogs with ACHES.
Given that a metabolic hallmark of ACHES is reduced circulating amino acids in the blood and profound amino acid loss in the urine, feeding a diet high in protein has previously been considered a mainstay of medical management [1,4,11]. The present study highlights the protein inclusions present in the diet may not be routinely achievable with a commercially available diet. Only 1/10 commercially available diets (Hill’s a/d) contained a protein content higher than the minimum protein content in the home-cooked group. As expected, when amino acids were individually assessed in the nutrient profiles, home-cooked diets contained significantly greater amounts of nearly all measured amino acids than the commercially available diets. Although the mechanism of hypoaminoacidemia and profound aminoaciduria remains to be identified in ACHES, hypoaminoacidemia in dogs with a glucagon-producing neoplasm in a report of two cases with SND is attributable to hyperglucagonemia [12]. Genetic mutations in people related to renal amino acid transporter defects and altered amino acid host metabolism have been associated with dermatologic lesions [13,14]. Importantly, these human clinical scenarios employ differing nutritional strategies where enhanced dietary protein intake can be recommended in the case of Hartnup disorder [13,15,16] to overcome renal loss of tryptophan; however, in the case of lysinuric protein intolerance (LPI), protein restriction is recommended [14,17]. While lysinuria has been demonstrated as a significant feature for dogs with ACHES [11], it is important to note that other aminoacidurias occur in ACHES and differ from human LPI.
The other nutrient identified from our data to provide a survival benefit for dogs with ACHES was sodium. This relationship was unexpected, and the authors can only speculate on a physiologic link to this finding. Many intestinal mechanisms for amino acid absorption are sodium-dependent [18], so this survival benefit may reflect improved amino acid absorption facilitated by sodium. Our study found no significant difference in sodium content between home-cooked and commercially available diets, although the median sodium content was higher in commercial diets. So, while theoretically, sodium-coupled intestinal amino acid absorption would benefit ACHES patients, there is no reason to suspect from our dataset that any patient had a deficiency of sodium that would have reduced the capacity of amino acid absorption in a healthy individual.
The nutrient identified as having the highest hazard ratio for reduced survival duration in ACHES patients was calcium, although this did not reach significance, and the CI indicated poor precision. However, there was a significant difference in calcium between home-cooked and commercial diets. Though calcium and protein metabolism can be linked at multiple locations, including intestinal absorption and renal tubular reabsorption [19], there does not appear to be an apparent physiologic link that would explain higher dietary calcium reducing survival duration in ACHES patients. The underlying mechanism of amino acid dysregulation in ACHES remains unknown, and it is possible that dietary calcium could play a role in that mechanism. All home-cooked and commercially available diets in the present study provided at least the NRC recommended allowance for calcium except for one home-cooked diet that provided 0.92 g/1000 kcal instead of the recommended 1.0 g/1000 kcal, which is nearly twice the minimal requirement of 0.5 g/1000 kcal. Despite the equivocal relationship between calcium and survival, we included this nutrient in our target nutrient ranges because there was a trend toward increased risk of death with higher calcium inclusions that were well above the recommended allowance.
While vitamin E was higher in commercial diets, it was not associated with increased or decreased survival risk. This is worth noting as Vitamin E is often supplemented for hepatoprotection in dogs; however, limited data support its use for this specific indication [20]. Therefore, although vitamin E would provide some additional antioxidant support, there is currently no clear indication that additional supplementation should be provided to ACHES patients on a routine basis.
Total dietary fat content was associated with reduced survival; however, total fat content did not significantly differ between commercial and home-cooked diets. Due to the extent of hepatic change in ACHES patients, it is possible a degree of atypical fat absorption and metabolic processing exists in ACHES cases compared to healthy dogs. However, to mechanistically determine a relationship between dietary fat intake and disease outcome, serum metabolomic analysis would be required to understand how the host lipid profile is altered at a higher resolution and predict metabolic consequences in ACHES patients. Another factor is that on a caloric basis, increasing dietary fat is balanced by a reduction in protein, carbohydrate, or both. Therefore, the association with higher fat and reduced survival may be an epiphenomenon linked to lower dietary protein inclusions on a caloric basis. This is supported by the short survival time (8 days) of the dog fed a diet with one of the lowest protein inclusions (42 g/1000 kcal) and relatively high fat (53 g/1000 kcal).
Also, all but one of the home-cooked diets in this study were formulated by an individual trained to formulate a complete and balanced veterinary diet through a veterinary nutrition residency. The study authors recommend that any application of a home-cooked diet for veterinary therapeutic use, regardless of ACHES status, be formulated by an adequately trained individual, as it is widely documented that home-prepared diets contain unintended nutritional deficiencies when prepared by an untrained individual [21].
Our study is limited in scope primarily by the paucity of complete dietary profile information. The original study cohort where a survival benefit was identified for home-cooked diets included 38 ACHES patients, with 21 fed commercial diets and 17 fed home-cooked diets [4]. Of those, four in the commercial diet group did not survive for longer than 30 days. This introduces possible bias in evaluating the possible survival benefits of diet, given that the patients not surviving longer than 30 days all fell within the commercial diet group and may have had more severe underlying disease. For this reason, the cohort of 34 patients surviving over 30 days was also assessed, and the survival benefit of patients receiving a home-cooked diet remained. Additionally, in that study, there was no difference in survival when dogs were stratified by skin lesion severity, suggesting that biases in treatment decisions based on clinical severity did not translate to a significant difference in survival, while the intervention of a home-cooked diet did [4]. In this current follow-up analysis, adequate dietary nutrient profiles could only be obtained for 8/17 home-cooked diet and 10/21 commercial diet patients in the original study, limiting the scope of the analysis. It is important to note that 2/10 commercial diet profiles that could be obtained were from patients who did not survive longer than 30 days, which may introduce a degree of bias to the analysis, and the findings should be interpreted as such. Still, given that the original survival analysis [4] showed a survival benefit for dogs receiving home-cooked diets when all dogs were included and when only dogs surviving longer than 30 days were included, these two dogs were included in the present analysis to capture as large a dietary picture as possible. Furthermore, of the commercial diets, a complete nutrient profile commensurate to the profiles for home-cooked diets could only be obtained for 5/10 commercial diets, with limited nutrient profile information obtained for the remaining 5/10 diets. Overall, any results with small sample sizes need to be interpreted cautiously. Small cohorts are prone to extreme results and findings that do not reach statistical significance, and spuriously significant results are more likely to occur.
While care was taken during the initial case selection for the retrospective cohort study [1,4], additional communication with owners and primary veterinarians helped ensure dietary histories within the medical records were accurate and corresponded with feeding at home. Still, there remains a possibility that both the retrospective nature of collecting dietary information and day-to-day variation in dietary regimen at home predispose to a degree of inaccuracy that would be strengthened in a prospective, controlled trial. Future studies that build upon the findings presented here should aim for robust use of randomization, controls, blinding, and prospective study [22] to strengthen the body of literature regarding dietary treatment in ACHES.
Optimal treatment of ACHES is not limited to diet; it also involves additional pillars that include amino acid infusions and dietary supplements, which have been shown to impact survival [4]. Moreover, it is important to consider this is a disease process with a high caregiver burden [23] that is both emotional and financial, thus making survival analyses inherently challenging. Thus, our data should also be interpreted with the lens that multiple factors impact survival, diet being a main driver, and that not all owners of an ACHES patient will pursue optimal treatment. This may introduce some selection bias as owners who elect to do a home-cooked diet may be more likely to pursue all the additional components of optimal ACHES treatment (home-cooked diet, ≥2 amino acid infusions, ≥3 prioritized supplements) [4] compared to owners who elect to feed a commercial diet. However, only 9/41 dogs in the previous study were optimally treated, illustrating the limits of any such bias. Moreover, within the presented cohort, discussions of dietary management for dogs remaining on commercial diets were up to the primary overseeing clinician, and owners did not necessarily receive direct input from a veterinary nutritionist. Still, here we demonstrate that the high protein content achieved in a home-cooked diet exceeds what was readily available in the commercial diets used through this cohort, even if a high protein commercial diet is selected. However, it is conceivable that commercial diets conforming to nutrient inclusions appropriate for dogs with ACHES could be associated with similar outcomes
5. Conclusions
Our data demonstrate the importance of high protein achieved through home-cooked diets in the medical management of ACHES. We show that protein is significantly greater in home-cooked diets compared to commercially available diets and was associated with a modest survival benefit. The finding that higher sodium was associated with longer survival warrants further investigation as a nutritional modification for dogs with this syndrome. Overall, this is the first description in the body of literature to help inform targets for dietary nutrient composition for patients with ACHES, a rare disease recognized to be optimally managed in part through nutrition.
Author Contributions
Conceptualization, J.P.L. and J.C.R.; methodology, J.C.R., E.L., M.G.C., M.A. and J.P.L.; formal analysis, J.P.L. and J.C.R.; investigation, J.C.R., E.L., M.A., M.G.C. and J.P.L.; resources, J.P.L.; data curation, J.C.R., E.L. and M.A.; writing—original draft preparation, J.C.R., J.P.L. and E.L.; writing—review and editing, J.C.R., E.L., M.G.C., M.A. and J.P.L. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The animal study protocol was approved by Cornell University’s Institutional Animal Care and Use Committee (2017-0094).
Informed Consent Statement
Not applicable.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors on request.
Conflicts of Interest
Cline is a Senior Manager of Veterinary Medical Communications at Nestlé Purina PetCare. Her position posed no conflict of interest for this study.
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Figure 1.
Volcano plot of significant dietary features identified in a retrospective cohort of dogs with aminoaciduric canine hypoaminoacidemic hepatopathy syndrome (ACHES). Multiple Mann–Whitney tests compared nutrient inclusions between home-cooked and commercial diets. All p values were <0.01 for nutrients with −log10 q values > 2, indicated by the horizontal dotted line. Higher −log10 q values reflect smaller adjusted p values accounting for multiple comparisons. The vertical line represents the baseline for differences (as mean ranks) between nutrients between home-cooked and commercial diets. Nutrients of equal mean rank difference boxed together.
Figure 1.
Volcano plot of significant dietary features identified in a retrospective cohort of dogs with aminoaciduric canine hypoaminoacidemic hepatopathy syndrome (ACHES). Multiple Mann–Whitney tests compared nutrient inclusions between home-cooked and commercial diets. All p values were <0.01 for nutrients with −log10 q values > 2, indicated by the horizontal dotted line. Higher −log10 q values reflect smaller adjusted p values accounting for multiple comparisons. The vertical line represents the baseline for differences (as mean ranks) between nutrients between home-cooked and commercial diets. Nutrients of equal mean rank difference boxed together.
Figure 2.
Recommendations for nutrient targets for dogs with aminoaciduric canine hypoaminoacidemic hepatopathy syndrome (ACHES). Target ranges were determined as described in the methods. The authors recommend practitioners collaborate with, or refer clients to, a Board Certified Veterinary NutritionistTM to formulate home-cooked diet recipes that meet other nutrient targets consistent with life-stage or necessary modifications in cases with nutritionally relevant concurrent disease(s). Created with BioRender.com.
Figure 2.
Recommendations for nutrient targets for dogs with aminoaciduric canine hypoaminoacidemic hepatopathy syndrome (ACHES). Target ranges were determined as described in the methods. The authors recommend practitioners collaborate with, or refer clients to, a Board Certified Veterinary NutritionistTM to formulate home-cooked diet recipes that meet other nutrient targets consistent with life-stage or necessary modifications in cases with nutritionally relevant concurrent disease(s). Created with BioRender.com.
Table 1.
Summary of patient demographics in a retrospective cohort study from 2014–2020 of diets fed to dogs (n = 18) with aminoaciduric hypoaminoacidemic hepatopathy syndrome (ACHES). Note that dogs that died or were euthanized for reasons unrelated to ACHES (which was most often related to superficial necrolytic dermatitis [SND]) were censored for disease-specific survival analyses.
Table 1.
Summary of patient demographics in a retrospective cohort study from 2014–2020 of diets fed to dogs (n = 18) with aminoaciduric hypoaminoacidemic hepatopathy syndrome (ACHES). Note that dogs that died or were euthanized for reasons unrelated to ACHES (which was most often related to superficial necrolytic dermatitis [SND]) were censored for disease-specific survival analyses.
| Breed | Age (Year) | Sex | Weight (kg) | Diet Type | Commercial Diet Consumed | Survival Interval (Days) | Outcome |
|---|---|---|---|---|---|---|---|
| Bichon Frise | 11 | FS | 9.1 | COM | RC MP | 214 | E:ACHES/SND |
| Chihuahua | 10 | FS | 5.5 | COM | Blue Buffalo Salmon | 834 | C:Alive |
| Chihuahua | 14 | MN | 2.3 | COM | Hill’s a/d | 683 | E:Other (Septic Abdomen) |
| GSD Mix | 11 | MN | 23 | COM | RC HP | 107 | E: ACHES/SND |
| Lab | 7 | FS | 35 | COM | RC Duck and Potato | 523 | C: Alive |
| MBD | 11 | MN | 27.6 | COM | Purina EN Low Fat | 346 | E:Other (Multifactorial) |
| Terrier Mix | 13 | FS | 11.3 | COM | RC GI Low Fat | 68 | Censored:Alive |
| WHWT | 9 | MN | 7.5 | COM | Hill’s i/d | 6 | D:ACHES/SND |
| WHWT | 8 | MN | 9.6 | COM | Hill’s w/d | 1714 | C:Alive |
| WHWT | 9 | MN | 10.4 | COM | Hill’s l/d | 8 | E:ACHES/SND |
| GSP | 10 | MN | 38 | HC | - | 846 | E:Other (Pneumonia) |
| Husky/Lab Mix | 10 | FS | 33.5 | HC | - | 498 | E:Other (Multifactorial) |
| Maltese | 8 | FS | 6.6 | HC | - | 1783 | C:Alive |
| Poodle Mix | 11 | MN | 11 | HC | - | 1065 | E:Other (Abdominal Mass, Anemia) |
| SSD | 8 | MN | 13.6 | HC | - | 557 | E: ACHES/SND |
| SSD | 14 | MN | 12.1 | HC | - | 176 | E: Other (AKI) |
| Shih Tzu | 8 | FS | 4.8 | HC | - | 168 | E: ACHES/SND |
| WHWT | 11 | MN | 9.2 | HC | - | 238 | C: Alive |
AKI: Acute kidney injury, COM: Commercial diet, FS: Female spayed, GSD: German Shepherd Dog, GSP: German Shorthaired Pointer, HC: Home-cooked diet, MBD: Mixed-breed dog, MN: Male neutered, SSD: Shetland Sheepdog, WHWT: West Highland White Terrier. Outcomes: E = euthanized, C = censored, D = died.
Table 2.
Summary of nutrient profiles in a retrospective cohort study of home-cooked (n = 8) or commercial (n = 10) diets fed to dogs with aminoaciduric hypoaminoacidemic hepatopathy syndrome. Parenthetical n values in the Median (n) column refer to the number of diet profiles for which data for the corresponding nutrient were available. All nutrient units are listed on a per 1000 kcal basis.
Table 2.
Summary of nutrient profiles in a retrospective cohort study of home-cooked (n = 8) or commercial (n = 10) diets fed to dogs with aminoaciduric hypoaminoacidemic hepatopathy syndrome. Parenthetical n values in the Median (n) column refer to the number of diet profiles for which data for the corresponding nutrient were available. All nutrient units are listed on a per 1000 kcal basis.
| Nutrient | Unit | NRC RA 1 | Home-Cooked Diets | Commercial Diets | ||||
|---|---|---|---|---|---|---|---|---|
| Median (n) | Min | Max | Median (n) | Min | Max | |||
| Protein | g | 25-* | 111.4 (8) | 88.85 | 136.47 | 61.51 (10) | 39 | 90 |
| Arginine | g | 0.88-* | 5.87 (8) | 4.2 | 7.28 | 3.55 (6) | 2.64 | 4.2 |
| Histidine | g | 0.48-* | 2.9 (8) | 2.11 | 3.75 | 1.36 (5) | 0.8 | 1.6 |
| Isoleucine | g | 0.95-* | 4.79 (8) | 3.59 | 6.39 | 2.2 (5) | 1.6 | 2.38 |
| Leucine | g | 1.7-* | 7.15 (8) | 5.22 | 9.11 | 3.96 (5) | 3 | 4.19 |
| Lysine | g | 0.88-* | 7.6 (8) | 5.55 | 10.24 | 2.66 (6) | 1.7 | 3.88 |
| Methionine | g | 0.83-* | 2.51 (8) | 1.84 | 3.35 | 1.68 (6) | 0.9 | 2.1 |
| Methionine-cystine | g | 1.63-* | 3.82 (8) | 2.81 | 4.92 | 2.38 (6) | 1.51 | 2.7 |
| Phenylalanine | g | 1.13-* | 3.79 (8) | 2.94 | 4.89 | 2.4 (5) | 1.8 | 2.56 |
| Phenylalanine-tyrosine | g | 1.85-* | 6.88 (8) | 5.27 | 8.97 | 4.32 (5) | 3.32 | 4.99 |
| Threonine | g | 1.08-* | 3.97 (8) | 2.91 | 5.18 | 2.13 (5) | 1.5 | 2.42 |
| Tryptophan | g | 0.35-* | 1.07 (8) | 0.53 | 1.7 | 0.7 (6) | 0.4 | 0.75 |
| Valine | g | 1.23-* | 4.7 (8) | 3.51 | 6.07 | 2.7 (5) | 2 | 2.96 |
| Total fat | g | 13.8–77.5 | 34.5 (8) | 19.23 | 52.8 | 37.35 (10) | 17.4 | 67 |
| 18:2 undifferentiated (linoleic acid) | g | 2.8–16.3 | 4.93 (8) | 3.98 | 13.92 | 6.9 (5) | 3.3 | 11.4 |
| Choline | mg | 419-* | 525.56 (8) | 153.23 | 756.27 | 621.25 (6) | 414 | 719.9 |
| Folate | mcg | 67.5-* | 493.45 (8) | 84.37 | 1017 | 3.79 (6) | 2.35 | 745.9 |
| Niacin | mg | 4.25-* | 46.59 (8) | 29.35 | 59.05 | 8.85 (6) | 5 | 268.4 |
| Pantothenic acid | mg | 3.75–5000 | 8.82 (8) | 4.22 | 18.05 | 10.52 (6) | 5.21 | 41.9 |
| Riboflavin | mg | 1.3–375 | 1.98 (8) | 1.55 | 3.59 | 1.74 (6) | 1.3 | 13.8 |
| Thiamin | mg | 0.56–450 | 1.79 (8) | 0.59 | 6.17 | 3.34 (6) | 1.1 | 14.1 |
| Vitamin A, RAE | mcg | 379–16,000 | 2870.52 (8) | 308.56 | 4561.1 | 1840.5 (7) | 196 | 2258 |
| Vitamin B12 | mcg | 8.75-* | 33.17 (8) | 4.24 | 71.15 | 22.38 (5) | 20 | 40 |
| Vitamin B6 | mg | 0.375–125 | 4.51 (8) | 1.65 | 9.53 | 8.2 (5) | 1.7 | 22.1 |
| Vitamin D | IU | 136–800 | 678.35 (8) | 57.32 | 1818.2 | 258.85 (6) | 201 | 762 |
| Vitamin E (alpha-tocopherol) | IU | 7.5–250 | 32.42 (8) | 26.04 | 89.6 | 172 (10) | 151 | 211.5 |
| Vitamin K (phylloquinone) | mg | 0.41-* | 0.13 (8) | 0.03 | 0.49 | 0 (6) | 0 | 0.1 |
| Calcium | g | 1-* | 1.39 (8) | 0.92 | 2.81 | 2.54 (10) | 1.3 | 3.3 |
| Chloride | g | 0.3–5.875 | 1.28 (8) | 0.69 | 1.64 | 1.93 (6) | 1.2 | 2.5 |
| Copper | mg | 1.5-* | 1.16 (8) | 0.39 | 2.99 | 4.35 (6) | 1.5 | 9.1 |
| Iodine | mg | 0.22–1 | 0.24 (8) | 0.18 | 0.64 | 1.1 (5) | 0.7 | 1.4 |
| Iron | mg | 7.5-* | 21.84 (8) | 14.73 | 34.7 | 35.2 (5) | 25.3 | 50.7 |
| Magnesium | g | 0.15-* | 0.24 (8) | 0.17 | 0.29 | 0.2 (9) | 0.19 | 0.3 |
| Manganese | mg | 1.2-* | 2.95 (8) | 1.18 | 6.45 | 20.3 (5) | 7.56 | 24.2 |
| Phosphorus | g | 0.75-* | 1.07 (8) | 0.75 | 2.36 | 2.0 (9) | 1 | 2.4 |
| Potassium | g | 1-* | 1.76 (8) | 1.12 | 3.26 | 2.25 (10) | 1.7 | 2.9 |
| Selenium | mg | 0.09-* | 0.14 (8) | 0.11 | 0.21 | 0.1 (5) | 0.07 | 179 |
| Sodium | g | 0.2–3.75 ** | 0.81 (8) | 0.5 | 1.03 | 1.1 (10) | 0.42 | 1.82 |
| Zinc | mg | 15-* | 23.48 (8) | 17.3 | 51.25 | 61.98 (7) | 1.05 | 69.4 |
| EPA + DHA (omega-3 fatty acids) | g | 0.11–2.8 | 1.75 (8) | 1.16 | 2.01 | 0.75 (7) | 0 | 2.24 |
NRC = National Research Council; 1 Range of Recommended Allowance to Safe Upper Limit; * No Safe Upper Limit established; ** Safe Upper Limit based on >15 g/kg dry matter (4000 kcal/kg assumption).
Table 3.
Cox proportional hazard ratios of associations between nutrient inclusions as continuous variables and patient outcomes.
Table 3.
Cox proportional hazard ratios of associations between nutrient inclusions as continuous variables and patient outcomes.
| Parameter | Hazard Ratio Estimate | 95% Confidence Interval (Profile Likelihood) | p Value |
|---|---|---|---|
| Protein (g/1000 kcal) 1 | 0.92 | 0.82 to 1.0 | 0.043 * |
| Total fat (g/1000 kcal) | 1.15 | 1.02 to 1.37 | 0.043 * |
| Vitamin E (alpha-tocopherol, IU) | 0.96 | 0.90 to 1.005 | 0.14 |
| Calcium (g/1000 kcal) | 9.92 | 1.02 to 201.0 | 0.067 |
| Potassium (g/1000 kcal) | 1.21 | 0.08 to 34.09 | 0.9 |
| Sodium (g/1000 kcal) | 0.02 | <0.01 to 0.38 | 0.037 * |
1 p value for protein based on a one-tailed hypothesis, all other parameters based on a two-tailed hypothesis. * Indicates significance. A hazard ratio < 1.0 indicates a corresponding proportional reduced risk of death/euthanasia (increased survival) with every 1 unit increase in dietary inclusions of the corresponding variable. A hazard ratio > 1.0 indicates a corresponding proportional increased risk of death/euthanasia (decreased survival) with every 1 unit increase in dietary inclusions of the corresponding variable.
Table 4.
Cox proportional hazard ratios of associations between nutrient inclusions dichotomized by nutrient target cutoffs and patient outcomes in a retrospective cohort study of diets fed to dogs with aminoaciduric hypoaminoacidemic hepatopathy syndrome. The second round of validation was pursued to improve the model by reducing the low dietary sodium target cutoff.
Table 4.
Cox proportional hazard ratios of associations between nutrient inclusions dichotomized by nutrient target cutoffs and patient outcomes in a retrospective cohort study of diets fed to dogs with aminoaciduric hypoaminoacidemic hepatopathy syndrome. The second round of validation was pursued to improve the model by reducing the low dietary sodium target cutoff.
| Round 1 Validation | Round 2 Validation | |||||
|---|---|---|---|---|---|---|
| Parameter | Hazard Ratio Estimate | 95% Confidence Interval (Profile Likelihood) | p Value | Hazard Ratio Estimate | 95% Confidence Interval (Profile Likelihood) | p Value |
| Protein (<90 g/1000 kcal) | 16.1 | 1.8 to 499 | 0.025 * | 20.8 | 1.8 to 718.6 | 0.02 * |
| Total fat (≥40 g/1000 kcal) | 33.0 | 2.0 to 1314 | 0.013 * | 25.90 | 1.6 to 981.5 | 0.018 * |
| Calcium (≥2.8 g/1000 kcal) | 6.1 | 0.73 to 130.7 | 0.07 | 4.7 | 0.6 to 96.3 | 0.09 |
| Sodium (<0.8 g/1000 kcal) | 8.0 | 0.88 to 193.0 | 0.05 | - | - | - |
| Sodium (<0.7 g/1000 kcal) | - | - | - | 12.9 | 1.5 to 285.6 | 0.018 * |
All p values were based on a one-tailed hypothesis. * Indicates significance.
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Rowe, J.C.; Luo, E.; Cline, M.G.; Astor, M.; Loftus, J.P. Dietary Nutrient Evaluations in a Cohort of Dogs with Aminoaciduric Canine Hypoaminoacidemic Hepatopathy Syndrome Inform Dietary Targets for Protein, Fat, Sodium, and Calcium. Pets 2024, 1, 216-227. https://doi.org/10.3390/pets1030016
AMA Style
Rowe JC, Luo E, Cline MG, Astor M, Loftus JP. Dietary Nutrient Evaluations in a Cohort of Dogs with Aminoaciduric Canine Hypoaminoacidemic Hepatopathy Syndrome Inform Dietary Targets for Protein, Fat, Sodium, and Calcium. Pets. 2024; 1(3):216-227. https://doi.org/10.3390/pets1030016
Chicago/Turabian StyleRowe, John C., Emmy Luo, Martha G. Cline, Michael Astor, and John P. Loftus. 2024. "Dietary Nutrient Evaluations in a Cohort of Dogs with Aminoaciduric Canine Hypoaminoacidemic Hepatopathy Syndrome Inform Dietary Targets for Protein, Fat, Sodium, and Calcium" Pets 1, no. 3: 216-227. https://doi.org/10.3390/pets1030016
