What outcomes should be measured in feline chronic kidney disease treatment trials? Establishing a core outcome set for research.

Chronic Kidney Disease (CKD) is an important cause of feline morbidity and mortality. There is currently no agreement on which outcomes are most important in CKD treatment trials to assist evidence-based decision making. Core Outcome Sets (COSs) originated in human healthcare and are an agreed set of outcomes to be measured and reported as a minimum in any trial conducted relating to a particular disease. To establish a COS for feline CKD, this study used a systematic review and two consensus methodologies (an electronic Delphi (eDelphi), and an in-person consensus meeting), with an international panel of key stakeholders. The systematic review identified 104 unique published parameters, which were rated by panellists in round 1 of the eDelphi. Panellists were also asked to suggest additional parameters. In round 2 these additional parameters were rated and any parameters not understood by >10 % of panellists in round 1 were redefined and re-rated. Parameters reaching consensus in rounds 1 and 2 were removed from round 3, when all remaining parameters were re-rated by panellists who could view their own previous rating alongside the median rating of the whole panel. To reach inclusion in the COS, parameters had to be rated 8 or 9 on a Likert scale of 1-9 (where 1 was not important and 9 was very important) by more than 80 % of panellists. In the consensus meeting, panellists discussed and re-rated borderline parameters and streamlined the final COS. Borderline parameters were those that had been closest to, but not achieved, the 80 % threshold for inclusion. The eDelphi panel (n = 73) rated 24/104 parameters highly enough for inclusion and proposed an additional 20 parameters, of which 3 reached the inclusion threshold. This totalled 27 parameters for inclusion. The consensus meeting panel (n = 16) rated an additional 6/20 borderline parameters highly enough for inclusion. During the streamlining process, 4 parameters were removed as one was considered not an outcome, and three were already addressed by other parameters. The remaining COS totalled 29 parameters. These were grouped into 9 core themes: clinical examination, quality of life, serum biochemistry, complete blood count, urinalysis, total amount of food eaten, CKD progression, survival time and cause of death. This is the first COS for feline medicine. In future treatment efficacy trials the COS will strengthen the evidence-base for this condition, by facilitating easier comparison of results between studies, and reduce research waste.

Thyroid and renal function in cats following low-dose radioiodine (111Mbq) therapy.

OBJECTIVES: To describe the effect of low-dose (111MBq) radioiodine therapy on thyroid and renal function in hyperthyroid cats over a 12-month follow-up period. MATERIALS AND METHODS: Client-owned hyperthyroid cats underwent low-dose radioiodine therapy and were followed-up for 12 months. Immediately before radioiodine treatment, and at 1, 6 and 12 months afterwards, total thyroxine, thyroid stimulating hormone, serum creatinine and glomerular filtration rate were measured. RESULTS: Fifteen of the 24 (63%) cats achieved euthyroidism following low-dose radioiodine treatment. The incidence of overt hypothyroidism was six of 24 (25%) cats. Of the six cats developing overt hypothyroidism, three had decreased renal function, with decreased glomerular filtration rate preceding azotaemia in two of these individuals. Transient overt or subclinical hypothyroidism before restoration of euthyroidism was not observed. CLINICAL SIGNIFICANCE: Low-dose radioiodine is effective treatment for hyperthyroidism in most cats but overt hypothyroidism may develop in some. Concurrent early decline in renal function may only be detected by measuring glomerular filtration rate rather than serum creatinine in some cats. Monitoring following radioiodine treatment should include total thyroxine and thyroid stimulating hormone and measurement of glomerular filtration rate should be considered in non-azotaemic cats.

Risk Factors for Development of Chronic Kidney Disease in Cats.

BACKGROUND: Identification of risk factors for development of chronic kidney disease (CKD) in cats may aid in its earlier detection. HYPOTHESIS/OBJECTIVES: Evaluation of clinical and questionnaire data will identify risk factors for development of azotemic CKD in cats. ANIMALS: One hundred and forty-eight client-owned geriatric (>9 years) cats. METHODS: Cats were recruited into the study and followed longitudinally for a variable time. Owners were asked to complete a questionnaire regarding their pet at enrollment. Additional data regarding dental disease were obtained when available by development of a dental categorization system. Variables were explored in univariable and multivariable Cox regression models. RESULTS: In the final multivariable Cox regression model, annual/frequent vaccination (P value, .003; hazard ratio, 5.68; 95% confidence interval, 1.83-17.64), moderate dental disease (P value, .008; hazard ratio, 13.83; 95% confidence interval, 2.01-94.99), and severe dental disease (P value, .001; hazard ratio, 35.35; 95% confidence interval, 4.31-289.73) predicted development of azotemic CKD. CONCLUSION: Our study suggests independent associations between both vaccination frequency and severity of dental disease and development of CKD. Further studies to explore the pathophysiological mechanism of renal injury for these risk factors are warranted.

Determination of extracellular fluid volume in healthy and azotemic cats.

BACKGROUND: Methods for determining extracellular fluid volume (ECFV) are important clinically for cats. Bromide dilution has been studied in cats to estimate ECFV. Markers of GFR also distribute in ECFV and can be used for its measurement. HYPOTHESIS/OBJECTIVES: The primary objective was to develop a method of determining ECFV from iohexol clearance in cats and evaluate agreement with that determined using bromide dilution. Additional objectives were to compare ECFV between azotemic and nonazotemic cats and evaluate appropriate methods of standardizing ECFV. ANIMALS: Client-owned cats with varying renal function. METHODS: Validation of ECFV determined from slope-intercept iohexol clearance was performed in 18 healthy nonazotemic cats. ECFV was then determined using the validated method and bromide dilution and agreement assessed. Appropriateness of standardization to body weight (BW) and body surface area (BSA) was evaluated. RESULTS: Extracellular fluid volume determined from slope-intercept iohexol clearance and bromide dilution was 0.84 ± 0.32 L and 0.85 ± 0.19 L (mean ± SD), respectively. There were wide limits of agreement between the methods (-0.58 to 0.54 L) and therefore, agreement was considered to be poor. ECFV did not differ significantly between azotemic and nonazotemic cats (P = .177). BSA was found to be the best method for standardizing ECFV measurement in cats. CONCLUSIONS AND CLINICAL IMPORTANCE: This study developed a method for determining ECFV from slope-intercept iohexol clearance which provides simultaneous assessment of renal function and an estimate of ECFV. ECFV does not differ between azotemic and nonazotemic cats, which suggests fluid volume loss or overload is not an important clinical feature in cats with mild chronic kidney disease.

A single sample method for estimating glomerular filtration rate in cats.

BACKGROUND: Validated methods of estimating glomerular filtration rate (GFR) in cats requiring only a limited number of samples are desirable. HYPOTHESIS/OBJECTIVES: To test a single sample method of determining GFR in cats. ANIMALS: The validation population (group 1) consisted of 89 client-owned cats (73 nonazotemic and 16 azotemic). A separate population of 18 healthy nonazotemic cats (group 2) was used to test the methods. METHODS: Glomerular filtration rate was determined in group 1 using corrected slope-intercept iohexol clearance. Single sample clearance was determined using the Jacobsson and modified Jacobsson methods and validated against slope-intercept clearance. Extracellular fluid volume (ECFV) was determined from slope-intercept clearance with correction for the 1 compartment assumption and by deriving a prediction formula for ECFV (ECFV Predicted ) based on the body weight. The optimal single sample method was tested in group 2. RESULTS: A blood sample at 180 minutes and ECFV Predicted were optimal for single sample clearance. Mean ± SD GFR in group 1 determined using the Jacobsson and modified Jacobsson formulae was 1.78 ± 0.70 and 1.65 ± 0.60 mL/min/kg, respectively. When tested in group 2, the Jacobsson method overestimated multisample clearance. The modified Jacobsson method (mean ± SD 2.22 ± 0.34 mL/min/kg) was in agreement with multisample clearance (mean ± SD 2.19 ± 0.34 mL/min/kg). CONCLUSIONS AND CLINICAL IMPORTANCE: The modified Jacobsson method provides accurate estimation of iohexol clearance in cats, from a single sample collected at 180 minutes postinjection and using a formula based on the body weight to predict ECFV. Further validation of the formula in patients with very high or very low GFR is required.

Fibroblast growth factor 23 in feline chronic kidney disease.

BACKGROUND: Fibroblast growth factor 23 (FGF-23) is a phosphaturic hormone involved in the pathogenesis of secondary renal hyperparathyroidism (SRHP) in humans. There are no published studies examining feline FGF-23. OBJECTIVES: Validation of a method for FGF-23 quantification in feline plasma and assessment of the associations among plasma FGF-23, PTH, creatinine, and phosphate concentrations in cats with chronic kidney disease (CKD). ANIMALS: One hundred nonazotemic and azotemic geriatric (>9 years) client-owned cats. METHODS: Retrospective cross-sectional study: Cats were categorized into 4 groups: control group (plasma creatinine (Cr) ≤2.0 mg/dL), stage 2 (Cr 2.1-2.8 mg/dL), stage 3 (Cr 2.9-5.0 mg/dL), stage 4 (Cr >5.0 mg/dL). Stages 2 and 3 were further subdivided based on International Renal Interest Society targets for plasma phosphate concentration (PO4 ): stage 2a (PO4 ≤4.5 mg/dL), stage 2b (PO4 >4.5 mg/dL), stage 3a (PO4 ≤5 mg/dL), stage 3b (PO4 >5 mg/dL). Plasma FGF-23 concentrations were measured by a human intact FGF-23 ELISA. Descriptive statistics and linear regression were performed. RESULTS: The ELISA demonstrated acceptable precision, reproducibility, and specificity. Plasma FGF-23 concentrations increased with increasing plasma creatinine concentrations and were significantly different between all groups (P < .008). Plasma FGF-23 concentrations were significantly higher in cats in stage 2b than stage 2a (P = .008) and in stage 3b than in stage 3a (P = .012). Phosphate, log creatinine, total calcium, log parathyroid hormone, and packed cell volume were all independent predictors of FGF-23. CONCLUSIONS AND CLINICAL IMPORTANCE: FGF-23 concentrations increase with increasing stage of feline CKD and might be a marker or mediator of feline SRHP.

Fibroblast growth factor 23 (FGF-23) concentrations in cats with early nonazotemic chronic kidney disease (CKD) and in healthy geriatric cats.

BACKGROUND: Fibroblast growth factor (FGF-23) has an important role in phosphate regulation. Its clinical relevance in cats with CKD has not been explored previously. HYPOTHESIS/OBJECTIVES: The study objectives were (1) to determine whether FGF-23 concentrations are increased in nonazotemic cats, cats which developed azotemia within 12 months of screening compared with cats that remained non-azotemic, and (2) to evaluate the relationships between FGF-23 and PTH and FGF-23 and glomerular filtration rate (GFR). ANIMALS: Sixty-two healthy client-owned geriatric cats, 14 of which developed azotemia during the 12-month follow-up period. METHODS: Healthy nonazotemic cats were recruited prospectively into the study and followed for 12 months. At the study end-point, cats were categorized into 3 groups according to plasma creatinine concentration. PTH, FGF-23, and additional biochemical variables were evaluated at baseline and after 12 months. GFR was measured by a corrected slope-intercept iohexol clearance method. RESULTS: FGF-23 concentrations at baseline were found to be significantly increased in cats that developed azotemia (P = .001) compared with cats that did not develop azotemia. A significant positive relationship was identified between FGF-23 and PTH, whereas the relationship between FGF-23 and GFR was negative. CONCLUSIONS AND CLINICAL IMPORTANCE: FGF-23 concentrations predicted development of azotemia in geriatric cats. Positive relationships between FGF-23 and PTH suggest an association between FGF-23 and renal secondary hyperparathyroidism.

Association of urinary cadmium excretion with feline hypertension.

Fifty client-owned senior cats (32 normotensive and 18 hypertensive) with renal function ranging from normal to moderately reduced were recruited into a prospective cross-sectional study exploring the association of urinary cadmium excretion and hypertension in cats. Heparinised plasma samples were collected and analysed for routine biochemical parameters. Urine samples were collected via cystocentesis and were analysed for cadmium concentrations using inductively coupled plasma mass spectrometry (ICP-MS). Blood pressure was measured using the Doppler method. Urinary cadmium concentrations were indexed to urinary creatinineconcentration. Comparison of urinary cadmium excretion was made between hypertensive and normotensive cats.The median (range) urinary cadmium concentration standardised to urinary creatinine concentration (UCdCr) in the normotensive and hypertensive cats was 0.08 (0.02 to 0.37) and 0.12 (0.02 to 1.38) nmol/mmol creatinine. The UCdCr was significantly higher in hypertensive compared with normotensive cats (P=0.016). UCdCr and plasma creatinine concentration remained independent predictors of hypertensive status in a logistic regression model. UCdCr and plasma creatinine concentration were not correlated (r=-0.01, P=0.956). These data suggest cadmium exposure and accumulation in cats may play a role in the development of feline hypertension.