The effect of the sodium-glucose cotransporter type-2 inhibitor dapagliflozin on glomerular filtration rate in healthy cats.

Sodium-glucose cotransporter type-2 inhibitors (SGLT2is) reduce glomerular hyperfiltration in diabetic people with early diabetic nephropathy. The objective of this report was to assess changes in glomerular filtration rate in healthy cats after treatment with a SGLT2i. Eight healthy research adult castrated male cats were used in a randomized, controlled, cross-over study design. We induced isolated renal tubular glucosuria by dosing cats with the SGLT2i dapagliflozin. The cats received by mouth 10 mg dapagliflozin or control every 24 h in each of the 4, 5-d trial periods that were separated by a 7-d washout period. We assessed glomerular filtration rate (iohexol clearance method), serum urea, creatinine, symmetric dimethylarginine, and 24-h sodium and chloride urinary excretion on the fifth day of each trial period. We analyzed the data with a mixed linear model that included the fixed effects of treatment (treated and control) and trial period, and the random effect of the cat. Compared with controls, cats treated with dapagliflozin had a significant increase in mean (±SE) glomerular filtration rate (3.1 ± 0.2 vs 2.5 ± 0.2 mL/kg/min; P = 0.01), whereas there were no significant differences in serum urea, creatinine and symmetric dimethylarginine, and 24-h urine sodium and chloride excretion. We propose that dapagliflozin-mediated delivery of sodium and glucose distal from the proximal convoluted tubule induced compensatory increased sodium absorption at the thick ascending loop of Henle that resulted in decreased sodium delivery to the distal tubule leading to tubuloglomerular feedback-mediated glomerular hyperfiltration. Future studies should determine if SGLT2is' renoprotective effect in people can be enhanced with the addition of a Na+-K+-Cl- diuretic and whether dapagliflozin will be useful in mitigating proteinuria and hypertension that follow glomerular hyperfiltration in diabetic companion animals in a similar mechanism as in people.

Variability of Symmetric Dimethylarginine in Apparently Healthy Dogs.

BACKGROUND: Symmetric dimethylarginine (SDMA) is a screening tool for early kidney dysfunction and monitoring treatment in cases of chronic kidney disease (CKD). There are no current studies describing the suitability of this test for use with published population-based reference intervals. HYPOTHESIS/OBJECTIVES: To determine the components of biological variability, the index of individuality (IOI), the critical difference between sequential measurements (CD ) and the number of measurements required to assess the homeostatic set point (HSP), for both SDMA and serum creatinine (sCr), in apparently healthy dogs. ANIMALS: Twenty apparently healthy adult dogs owned by clients or staff at a veterinary teaching hospital. METHODS: Prospective, observational study. Blood was collected from each dog on 9 occasions, and SDMA and sCr were measured in duplicate using commercially available assays. RESULTS: SDMA and sCr had intermediate and low IOI values of 0.87 and 0.28, respectively. The CD of SDMA and sCr, was 1.34 µg/dL and 0.89 µmol/L, respectively. The sample numbers required for estimation of an individual's HSP (with 90 and 95% CI) for SDMA and sCr were 8 and 45, and 2 and 12 sequential measurements, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Based on our findings, in comparison to sCr, SDMA is better suited for use with population-based reference intervals. False-negative test results could occur when comparing a single test result from an individual to such intervals. Ideally CD should be used with sequential measurements.

The Effect of Urine Concentration and pH on the Growth of Escherichia Coli in Canine Urine In Vitro.

BACKGROUND: Lower urinary tract infections are common in dogs, and Escherichia coli is the most common bacterial pathogen isolated. The literature has conflicting evidence regarding the inhibitory effects of urine concentration and pH on E. coli growth. HYPOTHESIS/OBJECTIVES: To determine the effect of different pH and urine concentrations on E. coli growth in vitro. ANIMALS: Voided urine samples from 10 apparently healthy spayed female dogs were used. METHODS: A matrix of 9 urine specific gravity (USG; 1.010, 1.020, and 1.030) and pH (5.5, 7.0, and 8.5) combinations was prepared by diluting and titrating filtered voided urine samples. Three E. coli isolates were obtained from urine of female dogs with signs of lower urinary tract infection and cultured at different urine pH and USG combinations in wells of a microtiter plate. The number of E. coli colony-forming units (CFU) per mL of urine was calculated after aerobic incubation of the urine at 37°C for 18 hours, and statistically compared. RESULTS: Significant differences were identified in the mean log CFU/mL among different combinations of pH and USG. The lowest log CFU/mL were observed in alkaline concentrated urine (pH 8.5 and USG 1.030). CONCLUSIONS AND CLINICAL IMPORTANCE: Escherichia coli in vitro growth was higher in neutral to acidic and diluted urine compared to alkaline and concentrated urine. The impact of non-alkalizing diluting diets on the incidence of E. coli lower urinary tract infections should be further explored.

Kinetics of Plasma Cell-Free DNA and Creatine Kinase in a Canine Model of Tissue Injury.

BACKGROUND: Cell-free DNA (cfDNA) comprises short, double-stranded circulating DNA sequences released from damaged cells. In people, cfDNA concentrations correlate well with disease severity and tissue damage. No reports are available regarding cfDNA kinetics in dogs. OBJECTIVES/HYPOTHESIS: Cell-free DNA will have a short biological half-life and would be able to stratify mild, moderate, and severe tissue injury. Our study aims were to determine the kinetics and biological half-life of cfDNA and to contrast them with those of creatine kinase (CK). ANIMALS: Three groups of 10 dogs undergoing open ovariohysterectomy, surgery for cranial cruciate ligament rupture (CCLR), or hemilaminectomy. METHODS: Plasma for cfDNA and CK analysis was collected at admission, at induction of anesthesia, postsurgery (time 0) and at 6, 12, 24, 36, 48, 60, and 72 hours after surgery. RESULTS: The biological half-life of plasma cfDNA and CK were 5.64 hours (95% confidence interval [CI 95], 4.36-7.98 hours) and 28.7 hours (CI95, 25.3-33.3 hours), respectively. In the hemilaminectomy group, cfDNA concentrations differed significantly from admission at 6-12 hours after surgery. Creatine kinase activity differed among the surgical groups and reached a peak 6 hours after surgery. In the ovariohysterectomy and CCLR groups, plasma CK activity 72 hours after surgery did not differ from admission activity of the ovariohysterectomy group. In contrast, in the hemilaminectomy group, plasma CK activity after 72 hours did not return to the ovariohysterectomy group admission activity. CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma CK activity has a longer biological half-life than previously thought. In contrast to plasma CK activity, cfDNA has a short half-life and could be a useful marker for peracute severe tissue injury.