Introduction There is a significant incidence of cats with renal disease (RD) and calcium oxalate (CaOx) kidney uroliths in domesticated cats. Foods which aid in the management of these diseases may be enhanced through understanding the underlying metabolomic changes. Objective Assess the metabolomic profile with a view to identifying metabolomic targets which could aid in the management of renal disease and CaOx uroliths. Method This is a retrospective investigation of 42 cats: 19 healthy kidney controls, 11 with RD, and 12 that formed CaOx nephroliths. Cats were evaluated as adults (2 through 7 years) and at the end of life for plasma metabolomics, body composition, and markers of renal dysfunction. Kidney sections were assessed by Pizzolato stain at the end of life for detection of CaOx crystals. CaOx stone presence was also assessed by analysis of stones removed from the kidney at the end of life. Results There were 791 metabolites identified with 91 having significant (p < 0.05, q < 0.1) changes between groups. Many changes in metabolite concentrations could be explained by the loss of renal function being most acute in the cats with RD while the cats with CaOx stones were intermediate between control and RD (e.g., urea, creatinine, pseudouridine, dimethylarginines). However, the concentrations of some metabolites differentiated RD from CaOx stone forming cats. These were either increased in the RD cats (e.g., cystathionine, dodecanedioate, 3-(3-amino-3-carboxypropyl) uridine, 5-methyl-2′-deoxycytidine) or comparatively increased in the CaOx stone forming cats (phenylpyruvate, 4-hydroxyphenylpyruvate, alpha-ketobutyrate, retinal). Conclusions The metabolomic changes show specific metabolites which respond generally to both renal diseases while the metabolomic profile still differentiates cats with RD and cats with CaOx uroliths.
The domestic cat is one of the most popular pets in the world. It is estimated that 89–92% of domestic cats in the UK are non-pedigree Domestic shorthair (DSH), Domestic longhair (DLH), or Domestic semi-longhair cats (DSLH). Despite their popularity, little is known of the UK non-pedigree cats’ population structure and breeding dynamics. Using a custom designed single nucleotide variant (SNV) array, this study investigated the population genetics of 1344 UK cats. Principal components analysis (PCA) and fastSTRUCTURE analysis verified that the UK’s DSH, DLH, and DSLH cats are random-bred, rather than admixed, mix breed, or crossbred. In contrast to pedigree cats, the linkage disequilibrium of these random-bred cats was least extensive and decayed rapidly. Homozygosity by descent (HBD) analysis showed the majority of non-pedigree cats had proportionally less of their genome in HBD segments compared to pedigree cats, and that these segments were older. Together, these findings suggest that the DSH, DLH, and DSLH cats should be considered as a population of random-bred cats rather than a crossbred or pedigree-admixed cat. Unexpectedly, 19% of random-bred cat genomes displayed a higher proportion of HBD segments associated with more recent inbreeding events. Therefore, while non-pedigree cats as a whole are genetically diverse, they are not impervious to inbreeding and its health risks.
Objectives Evaluate the effects of renal disease and calcium oxalate stone formation in cats. Methods 42 cats were evaluated from one year of age to end of life (21 spayed females and 21 neutered males). There were three groups evaluated: 12 calcium oxalate stone forming cats (CaOx), 11 cats with renal disease (RD) and 19 healthy kidney cats (H). Their condition was defined during life or at the time of death. After death both bioarchive samples and historical data were analyzed. Analysis of serum (calcium, urea, and creatinine), urine (specific gravity) and body composition (lean, fat, bone mineral and bone mineral density) was accomplished. Dual Energy X-ray analysis was used to measure body composition. The Proc Mixed and Proc GLM program of SAS (9.4) was used for statistical analysis. A p value less than or equal to 0.05 was used as a cutoff for statistical significance. Results At the time of death circulating symmetric dimethyl arginine (SDMA) concentration was 11.0a, 45.5c and 27.4b ug/dl for H, RD and CaOx respectively. Lean body mass was 3.5a, 2.8b and 3.4a kg (H, RD and CaOx respectively). Body lean was significantly correlated (P < 0.01) with bone mineral content and creatinine, however there was no lean by group interaction. Creatinine concentration was influenced by body lean, before accounting for lean change it was 1.0a, 6.0b and 3.0c mg/dl and after adjustment for body lean was 0.7a, 6.7b, and 2.9c mg/dl (H, RD and CaOx respectively). Bone mineral content was 125a, 133a, b and 140b grams (H, RD and CaOx respectively using lean as a covariant). There was a differential effect of age on circulating calcium and phosphorus concentration. As cats aged both the RD and CaOx groups had increasing calcium concentration with increasing age in comparison to H, The CaOx group had increased calcium and phosphorus when compared to both RD and H. Conclusions These data show that SDMA has the advantage of not being influenced by lean body mass (as contrasted to creatinine). The data also leads to the conclusion that nutritional intervention in support of oxalate stone forming cats should include support for appropriate calcium phosphorus homeostasis while nutritional support for cats with renal disease should include optimum support of lean body mass. Funding Sources This study was funded by Hill's Pet Nutrition, Inc.
Inflammation plays an important role in the initiation and subsequent progression of chronic kidney disease. An increase in inflammatory markers including cytokines as well as markers of oxidative stress is associated with reduced kidney function. Inflammatory markers and the underlying mechanisms that contribute to the pathophysiology of kidney disease are not clear and likely are multifactorial. Another feature associated with renal dysfunction and inflammatory response is the formation of calcium oxalate stones formed from the crystal deposits in the tubular epithelial cells. The aim of the present study was to investigate changes in gene expression in the renal cortex obtained from cats with kidney disease or calcium oxalate stone formers (CaOx) at necropsy in order to identify novel inflammatory biomarkers associated with renal dysfunction. At the time of death the circulating levels of creatinine as well as symmetric dimethyl arginine (SDMA), both markers of kidney decline in cats, were significantly higher in cats with renal disease (n=11) or stone‐forming cats (CaOx, n=12) when compared to controls (n=19). Using RNAseq in kidney tissue, we found a significant increase in the expression of IL‐16, a T‐cell chemoattractant, in both cats with kidney disease (6.72 fold) and stone formers (7.03 fold) compared to controls (both p<0.0001). There was also a significant increase in caspase recruitment domain family member 11 (CARD11), an activator of T and B‐lymphocytes and NFkB, in cats with kidney disease (9.2 fold) and stone formers (10 fold) compared to controls (p<0001). However, some differences between the kidney disease and CaOx groups were also observed. In cats with kidney disease there was an increased expression of LY9 (CD299), found in T and B‐cells and thymocytes, IL2Rg, a marker of lymphocyte activation, and SPP1 (Osteopontin), expressed in activated T and B‐cells (all >6‐fold) when compared to controls (p<0.0001) but such increased expression was not seen in CaOx cats. In summary, while IL‐16 was increased in both groups, our results indicate important molecular differences in the pathogenesis of kidney dysfunction in cats with kidney disease and stone formers, and that distinct lymphocyte markers may be involved in the persistent decline of kidney function. Our studies suggest that the optimal nutritional therapy to slow the progression of kidney dysfunction may be different for cats with kidney disease or stone formers. Support or Funding Information This study was funded by Hill’s Pet Nutrition, Inc
Objective Evaluate the effect of cats that formed oxalate stones during life on plasma metabolite concentration as compared to cats with healthy kidneys or cats with chronic kidney disease. Methods The development and end of life effects of renal disease and calcium oxalate stone formation was evaluated with 42 cats evaluated from one year of age to end of life (21 spayed females and 21 neutered males). Each cat was assigned to one of three groups: calcium oxalate stone forming cats (CaOx, n=12, confirmed by stone analysis), cats with renal disease (RD, n=11) and healthy kidney cats (H, n=19). Their condition was defined during life or at the time of death. Plasma samples were collected throughout life in annual physical exams and at the end of life. Plasma was stored at ‐80 oC until analyzed. Metabolomic analysis was completed by Metabolon (Durham, NC). Statistical analysis was completed on natural log transformed data using group as an independent variable, animal age as a continuous variable, and each cat as a random variable. A statistical cutoff of p<0.05 was used. Results There were 789 analytes measured. There were 144 metabolites with different concentrations when the RD group was compared to the H group (112 increased, 32 decreased). There were 130 with different concentrations when the CaOx group was compared to the H group (116 increased, 14 decreased). There were 69 with different concentrations between the CaOx group and the RD group (47 increased, 32 decreased. Both RD and CaOx had increased concentrations in circulating analytes known to increase with reduced renal function (creatinine, urea, pseduouridine). The CaOx cats had higher levels of 1‐palmitoyl‐GPI, 1‐stearoyl‐GPI, and mannitol/sorbitol when compared to the RD cats. The RD cats had higher levels of guanosine, guanine, inosine and hypoxanthine when compared to the CaOx cats. These higher levels was the result of increases in the RD cats and reduced concentrations in the CaOx cats (when compared to H). Conclusions The aberrant metabolism and clearance of purines in cats may be a significant component in the formation of calcium oxalate stone formation.
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